CN103649062A - Piperazine thiazole derivatives useful in the treatment of tauopathies such as alzheimer's disease - Google Patents
Piperazine thiazole derivatives useful in the treatment of tauopathies such as alzheimer's disease Download PDFInfo
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- CN103649062A CN103649062A CN201280034129.3A CN201280034129A CN103649062A CN 103649062 A CN103649062 A CN 103649062A CN 201280034129 A CN201280034129 A CN 201280034129A CN 103649062 A CN103649062 A CN 103649062A
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- ethyl
- piperazine
- thiadiazoles
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- 0 *c1n[s]c(N2CCN(*[Al]*)CC2)n1 Chemical compound *c1n[s]c(N2CCN(*[Al]*)CC2)n1 0.000 description 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/08—1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Abstract
The present invention relates to a compound of formula (IA), wherein G1 is lower alkyl; lower alkyl substituted by one or more halogens; cycloalkyl; tetrahydropyran-4-yl; phenethyl; phenethyl substituted by one or more halogens; phenoxymethyl; phenoxymethyl substituted by one or more halogens; benzyloxyethyl; benzyloxy-ethyl substituted by one or more halogens; or is -NR2R3; R2 is hydrogen or lower alkyl; R3 is lower alkyl; tetrahydropyran-4-yl; -CH2-cycloalkyl; or cycloalkyl optionally substituted by lower alkyl substituted by one or more halogens; or R2 and R3 form together with the N-atom to which they are attached a heterocycloalkyl group with 4 or 5 carbon atoms, which is optionally substituted by one or more substituents selected from halogen; or lower alkyl substituted by one or more halogens; X is -CH2- or -(CH2)2-; Ar is phenyl or pyridinyl; R4 is halogen; lower alkyl; lower alkyl substituted by one or more halogens; or lower alkoxy; n is 1 or 2; or to a pharmaceutically active salt thereof, to a stereoisomeric form, including an individual diastereoisomer or enantiomer of the compound of formula (IA) as well as to a racemic or non-racemic mixture thereof. The present invention also relates to the use of a compound of formula (IA) for treating certain neurodegenerative disorders characterized by cytotoxic TAU misfolding and/or aggregation.
Description
Invention field
The present invention relates to piperazine thiazole and they are used for the treatment of the purposes of some the neurodegenerative illness that is characterized as cytotoxic T AU malfolding and/or gathering.
Background of invention
TAU be can in conjunction with and the therefore stable and albumen that defines micro-tubular structure and work in neurone.By the phosphorylation of TAU, regulate the combination of TAU and microtubule, and the phosphorylation state of control TAU also therefore regulates some TAU phosphorylation sites of TAU and microtubule binding affinity and kinases is identified accordingly.
The hyperphosphorylation of TAU causes it with insoluble form, to assemble.(these of the TAU of hyperphosphorylation are assembled also referred to as PHF or " conjugate spirals filament ").The feature of Tau pathology is by insoluble aggregate or the polymkeric substance of the TAU of the hyperphosphorylation of the self-polymeric reaction formation of TAU monomer.
The importance that TAU assembles is its relevant cytotoxicity, and this cytotoxicity has reduced neuronic integrity and functional and finally cause disease symptoms.By resolving familial in TAU, suddenly change, the direct effect of TAU in seizure of disease clearly established, and described sudden change shows it is to cause very morning and the sometimes reason of the tau pathology of invasive form.This type of sudden change comprises the change of the aminoacid sequence of the TAU that direct or indirect promotion neurotoxicity is assembled.
Alzheimer's disease (Alzheimer's disease) is the most well known in these diseases, and in this disease, TAU is deposited in neurone with the form of neurofibrillary tangle (NFT).They are described with name Alois Alzheimer (one of its patient suffers from this illness) first.
The treatment of at present Tau pathology (comprising alzheimer's disease) being used only provides the benefit (symptomatic benefit) of symptom and does not affect potential nerve degeneration.
WO2007/090617 disclose be used for the treatment of the nucleoprotein disease of α-altogether replacement 1,2,4-thiadiazoles derivative, described α-nucleoprotein disease is for example Parkinson's disease (Parkinson's disease), diffusivity lewy body disease (Lewy body disease), traumatic brain injury, amyotrophic lateral sclerosis, Niemann-Pick disease (Niemann-Pick disease), hallerman-Streiff syndrome (Hallervorden-Spatz syndrome), mongolism (Down syndrome), neuroaxonal dystrophy, multiple system atrophy and alzheimer's disease altogether.
Be intended to suppress cytotoxic T AU malfolding and/or assemble to postpone or stop the treatment of progression of disease at present also infeasible.Therefore, need the new therapy of the potential molecular mechanism of the harmful TAU malfolding of target and/or gathering, to reduce neuronal cell apoptosis and/or the sex change of suffering from such as in the patient of the tau pathology of alzheimer's disease.
Summary of the invention
A first aspect of the present invention relates to IA compound or its pharmaceutical activity salt, relate to and comprise the single diastereomer of formula IA compound or the stereoisomeric forms in any ratio of enantiomorph and relate to its racemize or non-racemic mixture;
Wherein
G
1it is low alkyl group; The low alkyl group being replaced by one or more halogens; Cycloalkyl; Tetrahydropyran-4-base; Styroyl; The styroyl being replaced by one or more halogens; Phenoxymethyl; The phenoxymethyl being replaced by one or more halogens; Benzyloxy-ethyl; Benzyloxy-the ethyl being replaced by one or more halogens; Huo Shi – NR
2r
3;
R
2hydrogen or low alkyl group;
R
3it is low alkyl group; Tetrahydropyran-4-base;-CH
2-cycloalkyl; Or the cycloalkyl optionally being replaced by low alkyl group, described low alkyl group is replaced by one or more halogens; Or R
2and R
3together with the N atom connecting with them, form the heterocycloalkyl with 4 or 5 carbon atoms, described Heterocyclylalkyl is optionally replaced by the one or more substituting groups by being selected from halogen; Or the low alkyl group being replaced by one or more halogens;
X Shi – CH
2-Huo – (CH
2)
2-;
Ar is phenyl or pyridyl;
R
4it is halogen; Low alkyl group; The low alkyl group being replaced by one or more halogens; Or lower alkoxy;
N is 1 or 2;
Collateral condition be described compound not:
-5-(4-(3-luorobenzyl) piperazine-1-yl)-3-methyl isophthalic acid, 2,4-thiadiazoles and
-3-sec.-propyl-5-(4-(3-(trifluoromethyl) benzyl) piperazine-1-yl)-1,2,4-thiadiazoles.
A second aspect of the present invention relates to the method for the preparation of described according to a first aspect of the invention formula IA compound, and described method comprises formula
Compound and formula
Compound coupling is to obtain formula
Wherein definition is as described in a first aspect of the present invention; wherein PG is hydrogen or blocking group; such as tert-butoxycarbonyl (BOC), 9-fluorenyl methoxy carbonyl (FMOC) etc.; if and hal be halogen or or needs, gained compound is converted into pharmaceutically acceptable acid salt.
A third aspect of the present invention relates to and contains one or more described according to a first aspect of the invention compounds and the medicament of pharmaceutically acceptable vehicle.
A fourth aspect of the present invention relates to according to the medicament of the third aspect and is used for the treatment of and is selected from following disease: alzheimer's disease, pager's disease (Pick's disease), corticobasal degeneration, stein-leventhal syndrome, frontotemporal dementia FTD and parkinsonism (are connected to karyomit(e) 17, FTDP-17).
A fifth aspect of the present invention relates to the purposes in the medicament for the preparation of the following disease for the treatment of according to the compound of first aspect present invention: alzheimer's disease, pager's disease, corticobasal degeneration, stein-leventhal syndrome, frontotemporal dementia FTD and parkinsonism (are connected to karyomit(e) 17, FTDP-17).
A sixth aspect of the present invention relates to the method for the treatment of following disease: alzheimer's disease, pager's disease, corticobasal degeneration, stein-leventhal syndrome, frontotemporal dementia FTD and parkinsonism (are connected to karyomit(e) 17, FTDP-17), described method comprises as at the defined compound of using significant quantity of a first aspect of the present invention.
Describe in detail
In one embodiment, formula IA compound is contained in the present invention, wherein,
G
1it is low alkyl group; The low alkyl group being replaced by one or more halogens; Cycloalkyl; Tetrahydropyran-4-base; Styroyl; The styroyl being replaced by one or more halogens; Phenoxymethyl; The phenoxymethyl being replaced by one or more halogens; Benzyloxy-ethyl; Benzyloxy-the ethyl being replaced by one or more halogens; Huo Shi – NR
2r
3; Preferably, G
1c
1-7alkyl; The C being replaced by one or more halogens
1-7alkyl; C
3-6cycloalkyl; Tetrahydropyran-4-base; Styroyl; The styroyl being replaced by one or more halogens; Phenoxymethyl; The phenoxymethyl being replaced by one or more halogens; Benzyloxy-ethyl; Benzyloxy-the ethyl being replaced by one or more halogens; Huo Shi – NR
2r
3; G preferably
1it is low alkyl group; Cycloalkyl; Tetrahydropyran-4-base; The phenoxymethyl being replaced by one or more halogens; Benzyloxy-ethyl; Benzyloxy-the ethyl being replaced by one or more halogens; Huo Shi – NR
2r
3; Preferably, G
1it is low alkyl group; Cycloalkyl; The phenoxymethyl being replaced by one or more halogens; Benzyloxy-ethyl; Benzyloxy-the ethyl being replaced by one or more halogens; Huo Shi – NR
2r
3; Preferably, G
1it is low alkyl group; The phenoxymethyl being replaced by one or more halogens; Phenoxy group-the ethyl being replaced by halogen; Huo Shi – NR
2r
3; G preferably
1c
1-7alkyl; The phenoxymethyl being replaced by one or more halogens; The phenoxy group ethyl being replaced by one or more halogens; Huo Shi – NR
2r
3;
R
2hydrogen or low alkyl group; R preferably
2hydrogen or C
1-7alkyl
R
3it is low alkyl group; Tetrahydropyran-4-base;-CH
2-cycloalkyl; The cycloalkyl optionally being replaced by low alkyl group, described low alkyl group is replaced by one or more halogens; Or R
2and R
3together with the N atom connecting with them, form the heterocycloalkyl with 4 or 5 carbon atoms, described Heterocyclylalkyl is optionally replaced by the one or more substituting groups by being selected from halogen; Or the low alkyl group being replaced by one or more halogens; Preferably, R
3c
1-7alkyl; Tetrahydropyran-4-base;-CH
2-C
3-6cycloalkyl; Optionally by C
1-7the C that alkyl replaces
3-6cycloalkyl, described C
1-7alkyl is replaced by one or more halogens; Or R
2and R
3together with the N atom connecting with them, form the heterocycloalkyl with 4 or 5 carbon atoms, described Heterocyclylalkyl is optionally replaced by the one or more substituting groups by being selected from halogen; Or the C being replaced by one or more halogens
1-7alkyl; Or R
2and R
3the N atom being connected with them forms the heterocycloalkyl with 4 or 5 carbon atoms together, and described Heterocyclylalkyl is optionally replaced by the one or more substituting groups by being selected from halogen; Or the C being replaced by one or more halogens
1-7alkyl; Preferably, R
3it is tetrahydropyran-4-base;-CH
2-cycloalkyl; The cycloalkyl optionally being replaced by low alkyl group, described low alkyl group is replaced by one or more halogens; Or R
2and R
3together with the N atom connecting with them, form the heterocycloalkyl with 4 or 5 carbon atoms, described Heterocyclylalkyl is optionally replaced by the one or more substituting groups by being selected from halogen; Or the low alkyl group being replaced by one or more halogens; Preferably, R
3be the cycloalkyl optionally being replaced by low alkyl group, described low alkyl group is replaced by one or more halogens; Or R
2and R
3together with the N atom connecting with them, form the heterocycloalkyl with 4 or 5 carbon atoms, described Heterocyclylalkyl is optionally replaced by the one or more substituting groups by being selected from halogen; Or the low alkyl group being replaced by one or more halogens;
X Shi – CH
2-Huo – (CH
2)
2-; X Shi – (CH preferably
2)
2;
Ar is phenyl or pyridyl; Preferably Ar is phenyl;
R
4it is halogen; Low alkyl group; The low alkyl group being replaced by one or more halogens; Or lower alkoxy; R preferably
4it is halogen; C
1-7alkyl; The C being replaced by one or more halogens
1-7alkyl; Or C
1-7alkoxyl group; R preferably
4it is halogen; The low alkyl group being replaced by one or more halogens; Or lower alkoxy; R preferably
4it is halogen; Or lower alkoxy;
N is 1 or 2; Preferably, n is 1.
In one embodiment, the invention provides formula IA compound, wherein
G
1c
1-6alkyl; The C being replaced by one or more halogens
1-6alkyl; C
3-6cycloalkyl; Tetrahydropyran-4-base; Phenyl; The phenyl being replaced by one or more halogens; Phenoxymethyl; The phenoxymethyl being replaced by one or more halogens; Benzyloxy-ethyl; Benzyloxy-the ethyl being replaced by one or more halogens; Huo Shi – NR
2r
3; Preferably, G
1c
1-6alkyl; C
3-6cycloalkyl; Tetrahydropyran-4-base; The phenoxymethyl being replaced by one or more halogens; Benzyloxy-ethyl; Benzyloxy-the ethyl being replaced by one or more halogens; Or-NR
2r
3; G preferably
1c
1-6alkyl; C
3-6cycloalkyl; The phenoxymethyl being replaced by one or more halogens; Benzyloxy-ethyl; Benzyloxy-the ethyl being replaced by one or more halogens; Huo Shi – NR
2r
3; Preferably, G
1c
1-6alkyl; The phenoxymethyl being replaced by one or more halogens; Benzyloxy-ethyl; Benzyloxy-the ethyl being replaced by one or more halogens; Or-NR
2r
3;
R
2hydrogen or C
1-6alkyl;
R
3c
1-6alkyl; Tetrahydropyran-4-base;-CH
2-C
3-6cycloalkyl; Optionally by C
1-6the C that alkyl replaces
3-6cycloalkyl, described alkyl is replaced by one or more halogens; Or R
2and R
3together with the N atom connecting with them, form the heterocycloalkyl with 4 or 5 carbon atoms, described Heterocyclylalkyl is optionally replaced by the one or more substituting groups by being selected from halogen; Or the C being replaced by one or more halogens
1-6alkyl; Preferably, R
3it is tetrahydropyran-4-base;-CH
2-C
3-6cycloalkyl; Optionally by C
1-6the C that alkyl replaces
3-6cycloalkyl, described alkyl is replaced by one or more halogens; Or R
2and R
3together with the N atom connecting with them, form the heterocycloalkyl with 4 or 5 carbon atoms, described Heterocyclylalkyl is optionally replaced by the one or more substituting groups by being selected from halogen; Or the C being replaced by one or more halogens
1-6alkyl; Preferably, R
3optionally by C
1-6the C that alkyl replaces
3-6cycloalkyl, described alkyl is replaced by one or more halogens; R
2and R
3together with the N atom connecting with them, form the heterocycloalkyl with 4 or 5 carbon atoms, described Heterocyclylalkyl is optionally replaced by the one or more substituting groups by being selected from halogen; Or the C being replaced by one or more halogens
1-6alkyl;
X Shi – CH
2-Huo – (CH
2)
2-; X Shi – (CH preferably
2)
2;
Ar is phenyl or pyridyl; Preferably Ar is phenyl;
R
4it is halogen; C
1-6alkyl; The C being replaced by one or more halogens
1-6alkyl; Or C
1-6alkoxyl group; R preferably
4it is halogen; The C being replaced by one or more halogens
1-6alkyl; Or C
1-6alkoxyl group; R preferably
4it is halogen; Or C
1-6alkoxyl group;
N is 1 or 2; Preferably, n is 1.
In one embodiment, formula IA compound is contained in the present invention, wherein, and G
1be selected from: low alkyl group; Cycloalkyl; Tetrahydropyran-4-base; The phenoxymethyl being replaced by one or more halogens; Benzyloxy-ethyl; Benzyloxy-the ethyl being replaced by one or more halogens; Huo – NR
2r
3;
In another embodiment of the present invention, described compound has according to the structure described in formula IA, wherein G
1shi – NR
2r
3and R
3be the cycloalkyl optionally being replaced by low alkyl group, described low alkyl group is replaced by one or more halogens; Or R
2and R
3together with the N atom connecting with them, form the heterocycloalkyl with 4 or 5 carbon atoms, described Heterocyclylalkyl is optionally replaced by the one or more substituting groups by being selected from halogen; Or low alkyl group; The low alkyl group being replaced by one or more halogens.
In one embodiment, formula IA compound is contained in the present invention, wherein, and G
1be selected from: low alkyl group; Cycloalkyl; Tetrahydropyran-4-base; The phenoxymethyl being replaced by one or more halogens; Benzyloxy-ethyl; Benzyloxy-the ethyl being replaced by one or more halogens; Huo – NR
2r
3; And X Shi – (CH
2)
2; Yet G more particularly
1low alkyl group or the phenoxymethyl that replaced by one or more halogens; Yet G more particularly
1it is benzyloxy-ethyl; Or the phenoxymethyl being replaced by one or more halogens; Yet G more particularly
1the phenoxymethyl being replaced by one or more halogens.
In one embodiment, formula IA compound is contained in the present invention, wherein, and X Shi – (CH
2)
2.
In one embodiment, formula IA compound is contained in the present invention, and wherein Ar is phenyl.
In one embodiment, formula IA compound is contained in the present invention, wherein, and G
1be selected from: low alkyl group; Cycloalkyl; Tetrahydropyran-4-base; The phenoxymethyl being replaced by one or more halogens; Benzyloxy-ethyl; Benzyloxy-the ethyl being replaced by one or more halogens; Huo – NR
2r
3; With Ar be phenyl; Yet G more particularly
1low alkyl group or benzyloxy-ethyl; The phenoxymethyl being replaced by one or more halogens; Yet G more particularly
1the phenoxymethyl being replaced by one or more halogens.
In one embodiment, formula IA compound is contained in the present invention, wherein, and G
1be selected from: low alkyl group; Cycloalkyl; Tetrahydropyran-4-base; The phenoxymethyl being replaced by one or more halogens; Benzyloxy-ethyl; Benzyloxy-the ethyl being replaced by one or more halogens; Huo – NR
2r
3; With Ar be phenyl; Yet G more particularly
1low alkyl group or the phenoxymethyl that replaced by one or more halogens; Yet G more particularly
1it is low alkyl group.
In one embodiment, formula IA compound is contained in the present invention, wherein, and G
1be selected from: low alkyl group; Cycloalkyl; Tetrahydropyran-4-base; The phenoxymethyl being replaced by one or more halogens; Benzyloxy-ethyl; Benzyloxy-the ethyl being replaced by one or more halogens.
In another particular of the present invention, described compound has according to the structure described in formula IA, thus G
1shi – NR
2r
3.
In another particular of the present invention, described compound has according to the structure described in formula IA, thus G
1shi – NR
2r
3; R
2hydrogen; And R
3low alkyl group; Tetrahydropyran-4-base;-CH
2-cycloalkyl; Or the cycloalkyl optionally being replaced by low alkyl group, described low alkyl group is replaced by one or more halogens.
In another particular of the present invention, described compound has according to the structure described in formula IA, thus G
1shi – NR
2r
3; And R
2and R
3together with the N atom connecting with them, form the heterocycloalkyl with 4 or 5 carbon atoms, described Heterocyclylalkyl is optionally replaced by the one or more substituting groups by being selected from halogen; Or the low alkyl group being replaced by one or more halogens.
In another particular of the present invention, described compound has according to the structure described in formula IA, wherein G
1that benzyloxy-ethyl and the Ar optionally being replaced by one or more halogens is phenyl.
In another particular of the present invention, described compound has according to the structure described in formula IA, wherein G
1it is benzyloxy-ethyl; Ar is phenyl and X Shi – (CH
2)
2.
In another particular of the present invention, described compound has according to the structure described in formula IA, wherein G
1the phenoxymethyl being replaced by one or more halogens and Ar are phenyl.
In another particular of the present invention, described compound has according to the structure described in formula IA, wherein G
1the phenoxymethyl being replaced by one or more halogens; Ar is phenyl and X Shi – (CH
2)
2.
In another particular of the present invention, described compound has according to the structure described in formula IA, wherein G
1that low alkyl group and Ar are phenyl.
In another particular of the present invention, described compound has according to the structure described in formula IA, wherein G
1it is low alkyl group; Ar is phenyl and X Shi – (CH
2)
2.
In a particular of the present invention, described compound has according to the structure described in formula IA, thus G
1shi – NR
2r
3; And Ar is phenyl.
In a particular of the present invention, described compound has the structure of formula IA, thus G
1shi – NR
2r
3; Ar is phenyl and R
2and R
3together with the N atom connecting with them, form the heterocycloalkyl with 4 or 5 carbon atoms, described Heterocyclylalkyl is optionally replaced by the one or more substituting groups by being selected from halogen; Or the low alkyl group being replaced by one or more halogens.
In a particular of the present invention, described compound has the structure of formula IA, thus G
1shi – NR
2r
3; X Shi – (CH
2)
2-and R
2and R
3together with the N atom connecting with them, form the heterocycloalkyl with 4 or 5 carbon atoms, described Heterocyclylalkyl is optionally replaced by the one or more substituting groups by being selected from halogen; Or the low alkyl group being replaced by one or more halogens.
In a particular of the present invention, described compound has the structure of formula IA, thus G
1shi – NR
2r
3; Ar is phenyl; R
2and R
3together with the N atom connecting with them, form the heterocycloalkyl with 4 or 5 carbon atoms, described Heterocyclylalkyl is optionally replaced by the one or more substituting groups by being selected from halogen; Or the low alkyl group being replaced by one or more halogens; And X Shi – (CH
2)
2.
For example, the formula IA compound with structural formula I is contained in the present invention.
compound
R wherein
1have and G
1identical implication.
In a particular, the present invention relates to following compound, purposes, medicament and method:
E1. a formula I compound
Wherein
R
1it is low alkyl group; Cycloalkyl; Tetrahydropyran-4-base Huo Shi – NR
2r
3;
R
2hydrogen or low alkyl group;
R
3low alkyl group; Tetrahydropyran-4-base; CH
2-cycloalkyl or the cycloalkyl optionally being replaced by low alkyl group, described low alkyl group is replaced by one or more halogens;
Or R
2and R
3together with the N atom connecting with them, form the heterocycloalkyl with 4 or 5 carbon atoms, one or more substituting groups that described Heterocyclylalkyl is optionally selected from halogen or low alkyl group replace, and described low alkyl group is replaced by one or more halogens.
X Shi – CH
2-Huo – (CH
2)
2-;
Ar is phenyl or pyridyl;
R
4halogen, low alkyl group or the low alkyl group that replaced by one or more halogens.
N is 1 or 2;
Or relate to its pharmaceutically active salt, relate to and comprise the single diastereomer of formula I compound or the stereoisomeric forms in any ratio of enantiomorph and relate to its racemize or non-racemic mixture.
E2. according to the formula I compound described in E1, X Shi – (CH wherein
2)
2-.
E3. according to the formula I compound described in E2, described compound is
1-[3-(the fluoro-piperidin-1-yl of 4,4-bis-)-[1,2,4] thiadiazoles-5-yl]-4-[2-(4-methoxyl group-phenyl)-ethyl]-piperazine
1-[2-(the chloro-phenyl of 4-)-ethyl]-4-[3-(the fluoro-piperidin-1-yl of 4,4-bis-)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the chloro-phenyl of 4-)-ethyl]-4-[3-(the fluoro-pyrrolidin-1-yl of 3,3-bis-)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the chloro-phenyl of 4-)-ethyl]-4-[3-(4-fluoro-piperidine-1-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the chloro-phenyl of 4-)-ethyl]-4-[3-(4-trifluoromethyl-piperidin-1-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the chloro-phenyl of 4-)-ethyl]-4-(3-piperidin-1-yl-[1,2,4] thiadiazoles-5-yl)-piperazine
(5-{4-[2-(the chloro-phenyl of 4-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-cyclopropyl methyl-amine
(5-{4-[2-(the chloro-phenyl of 4-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-(tetrahydrochysene-pyrans-4-yl)-amine
(5-{4-[2-(the chloro-phenyl of 4-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-cyclohexyl-amine
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(the fluoro-piperidin-1-yl of 4,4-bis-)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(the fluoro-pyrrolidin-1-yl of 3,3-bis-)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(4-fluoro-piperidine-1-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(4-trifluoromethyl-piperidin-1-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-(3-pyrrolidin-1-yl-[1,2,4] thiadiazoles-5-yl)-piperazine
Cyclopropyl methyl-(5-{4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-amine
(5-{4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-(tetrahydrochysene-pyrans-4-yl)-amine
Cyclohexyl-(5-{4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-amine
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-(3-piperidin-1-yl-[1,2,4] thiadiazoles-5-yl)-piperazine
(5-{4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-(4-trifluoromethyl-cyclohexyl)-amine
Butyl-(5-{4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-ethyl-amine
1-(3-cyclohexyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(4-methoxyl group-phenyl)-ethyl]-piperazine
1-(3-cyclohexyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(3-methoxyl group-phenyl)-ethyl]-piperazine
1-(3-butyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(4-methoxyl group-phenyl)-ethyl]-piperazine
1-(3-cyclopropyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(4-methoxyl group-phenyl)-ethyl]-piperazine
1-(3-butyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(3-methoxyl group-phenyl)-ethyl]-piperazine
1-(3-cyclopropyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(3-methoxyl group-phenyl)-ethyl]-piperazine
1-[2-(the fluoro-phenyl of 4-)-ethyl]-4-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(4-methoxyl group-phenyl)-ethyl]-4-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(2-methoxyl group-pyridin-4-yl)-ethyl]-4-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine or
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
E4. according to the formula I compound described in any one in E1 – E3, wherein R
1low alkyl group, cycloalkyl or tetrahydropyran-4-base.
E5. according to the formula I compound described in E4, wherein compound is
1-(3-cyclohexyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(4-methoxyl group-phenyl)-ethyl]-piperazine
1-(3-cyclohexyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(3-methoxyl group-phenyl)-ethyl]-piperazine
1-(3-butyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(4-methoxyl group-phenyl)-ethyl]-piperazine
1-(3-cyclopropyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(4-methoxyl group-phenyl)-ethyl]-piperazine
1-(3-butyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(3-methoxyl group-phenyl)-ethyl]-piperazine
1-(3-cyclopropyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(3-methoxyl group-phenyl)-ethyl]-piperazine
1-[2-(the fluoro-phenyl of 4-)-ethyl]-4-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(4-methoxyl group-phenyl)-ethyl]-4-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(2-methoxyl group-pyridin-4-yl)-ethyl]-4-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine or
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
E6. according to the formula I compound described in any one in E1 – E3, wherein R
1shi – NR
2r
3.
E7. according to the formula I compound described in E6, wherein R
2hydrogen and R
3low alkyl group, tetrahydropyran-4-base ,-CH
2-cycloalkyl or the cycloalkyl optionally being replaced by low alkyl group, described low alkyl group is replaced by one or more halogens.
E8. according to the formula I compound described in E7, wherein compound is
(5-{4-[2-(the chloro-phenyl of 4-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-cyclopropyl methyl-amine
(5-{4-[2-(the chloro-phenyl of 4-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-(tetrahydrochysene-pyrans-4-yl)-amine
(5-{4-[2-(the chloro-phenyl of 4-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-cyclohexyl-amine
Cyclopropyl methyl-(5-{4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-amine
(5-{4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-(tetrahydrochysene-pyrans-4-yl)-amine
Cyclohexyl-(5-{4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-amine or
(5-{4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-(4-trifluoromethyl-cyclohexyl)-amine
E9. according to the formula I compound described in E6, wherein R
2and R
3together with the N atom connecting with them, form the heterocycloalkyl with 4 or 5 carbon atoms, one or more substituting groups that described Heterocyclylalkyl is optionally selected from halogen or low alkyl group replace, and described low alkyl group is replaced by one or more halogens.
E10. according to the formula I compound described in E9, described compound is:
1-[3-(the fluoro-piperidin-1-yl of 4,4-bis-)-[1,2,4] thiadiazoles-5-yl]-4-[2-(4-methoxyl group-phenyl)-ethyl]-piperazine
1-[2-(the chloro-phenyl of 4-)-ethyl]-4-[3-(the fluoro-piperidin-1-yl of 4,4-bis-)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the chloro-phenyl of 4-)-ethyl]-4-[3-(the fluoro-pyrrolidin-1-yl of 3,3-bis-)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the chloro-phenyl of 4-)-ethyl]-4-[3-(4-fluoro-piperidine-1-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the chloro-phenyl of 4-)-ethyl]-4-[3-(4-trifluoromethyl-piperidin-1-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the chloro-phenyl of 4-)-ethyl]-4-(3-piperidin-1-yl-[1,2,4] thiadiazoles-5-yl)-piperazine
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(the fluoro-piperidin-1-yl of 4,4-bis-)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(the fluoro-pyrrolidin-1-yl of 3,3-bis-)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(4-fluoro-piperidine-1-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(4-trifluoromethyl-piperidin-1-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-(3-pyrrolidin-1-yl-[1,2,4] thiadiazoles-5-yl)-piperazine or
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-(3-piperidin-1-yl-[1,2,4] thiadiazoles-5-yl)-piperazine
E11. prepare according to a method for the formula I compound described in E1, described method comprises
By formula
Compound and formula
Compound coupling is to obtain formula
Wherein definition, as E1 describes, if needed, is converted into pharmaceutically acceptable acid salt by the described compound obtaining.
E12. according to the compound described in any one in E1-E10, prepared by its method according to E11.
E13. according to the compound described in any one in E1-E10, it is as therapeutic active substance.
E14. a medicament, it is containing just like one or more compounds described in any one in E1-E10 and pharmaceutically acceptable vehicle.
E15. according to the medicament described in E14, the disease that wherein can be treated is that alzheimer's disease, pager's disease, corticobasal degeneration, stein-leventhal syndrome, frontotemporal dementia FTD and parkinsonism (are connected to karyomit(e) 17, FTDP-17).
E16. the compound as described in any one in E1-E10 in treatment the purposes in following disease, alzheimer's disease, pager's disease, corticobasal degeneration, stein-leventhal syndrome, frontotemporal dementia FTD and parkinsonism (are connected to karyomit(e) 17, FTDP-17).
E17. the compound as described in any one in E1-E10 is for the preparation of the purposes that is used for treating the medicament of following disease, alzheimer's disease, pager's disease, corticobasal degeneration, stein-leventhal syndrome, frontotemporal dementia FTD and parkinsonism (are connected to karyomit(e) 17, FTDP-17).
E18. a method that is used for the treatment of following disease, alzheimer's disease, pager's disease, corticobasal degeneration, stein-leventhal syndrome, frontotemporal dementia FTD and parkinsonism (are connected to karyomit(e) 17, FTDP-17), described method comprise use significant quantity as the defined compound of E1 – E10 any one.
E19. the present invention as described previously.
For example, formula I or IA compound, wherein G are contained in the present invention
1have as to R
1defined same implication, wherein
R
1it is low alkyl group; Cycloalkyl; Tetrahydropyran-4-base; Huo Shi – NR
2r
3; Preferably, R
1c
1-7alkyl; C
3-6cycloalkyl; Tetrahydropyran-4-base; Huo Shi – NR
2r
3; R preferably
1c
1-6alkyl; C
3-6cycloalkyl; Tetrahydropyran-4-base; Huo Shi – NR
2r
3; R preferably
1it is low alkyl group; Cycloalkyl; Huo Shi – NR
2r
3; R preferably
1it is low alkyl group; Huo Shi – NR
2r
3;
R
2hydrogen or low alkyl group; R preferably
2hydrogen or C
1-7alkyl; R preferably
2hydrogen or C
1-6alkyl;
R
3it is low alkyl group; Tetrahydropyran-4-base;-CH
2-cycloalkyl; The cycloalkyl optionally being replaced by low alkyl group, described low alkyl group is replaced by one or more halogens; Or R
2and R
3together with the N atom connecting with them, form the heterocycloalkyl with 4 or 5 carbon atoms, described Heterocyclylalkyl is optionally replaced by the one or more substituting groups by being selected from halogen; Or the low alkyl group being replaced by one or more halogens; R preferably
3c
1-7alkyl; Tetrahydropyran-4-base;-CH
2-C
3-6cycloalkyl; Optionally by C
1-7the C that alkyl replaces
3-6cycloalkyl, described C
1-7alkyl is replaced by one or more halogens; Or R
2and R
3together with the N atom connecting with them, form the heterocycloalkyl with 4 or 5 carbon atoms, described Heterocyclylalkyl is optionally replaced by the one or more substituting groups by being selected from halogen; Or the C being replaced by one or more halogens
1-7alkyl; R preferably
3c
1-6alkyl; Tetrahydropyran-4-base;-CH
2-C
3-6cycloalkyl; Optionally by C
1-6the C replacing
3-6cycloalkyl, described C
1-6alkyl is replaced by one or more halogens; Or R
2and R
3together with the N atom connecting with them, form the heterocycloalkyl with 4 or 5 carbon atoms, described Heterocyclylalkyl is optionally replaced by the one or more substituting groups by being selected from halogen; Or the C being replaced by one or more halogens
1-6alkyl; Preferably, R
3it is tetrahydropyran-4-base;-CH
2-cycloalkyl; The cycloalkyl optionally being replaced by low alkyl group, described low alkyl group is replaced by one or more halogens; Or R
2and R
3together with the N atom connecting with them, form the heterocycloalkyl with 4 or 5 carbon atoms, described Heterocyclylalkyl is optionally replaced by the one or more substituting groups by being selected from halogen; Or the low alkyl group being replaced by one or more halogens; R
3be the cycloalkyl optionally being replaced by low alkyl group, described low alkyl group is replaced by one or more halogens; Or R
2and R
3together with the N atom connecting with them, form the heterocycloalkyl with 4 or 5 carbon atoms, described Heterocyclylalkyl is optionally replaced by the one or more substituting groups by being selected from halogen; Or the low alkyl group being replaced by one or more halogens;
X Shi – CH
2-Huo – (CH
2)
2-; X Shi – (CH preferably
2)
2;
Ar is phenyl or pyridyl; Preferably Ar is phenyl;
R
4it is halogen; Low alkyl group; The low alkyl group being replaced by one or more halogens; Or lower alkoxy; R preferably
4it is halogen; C
1-7alkyl; Or the C being replaced by one or more halogens
1-7alkyl; Or C
1-7alkoxyl group; R preferably
4it is halogen; C
1-6alkyl; Or the C being replaced by one or more halogens
1-6alkyl; Or C
1-6alkoxyl group; R preferably
4it is halogen; The low alkyl group being replaced by one or more halogens; R preferably
4it is halogen;
N is 1 or 2; Preferably, n is 1.
In another more specific embodiment, compound of the present invention is contained formula I or IA compound, wherein, and R
1be selected from: low alkyl group, cycloalkyl, tetrahydropyran-4-base; Huo – NR
2r
3;
In another particular of the present invention, described compound has according to the structure described in formula I or IA, wherein R
1shi – NR
2r
3and R
3be the cycloalkyl optionally being replaced by low alkyl group, described low alkyl group is replaced by one or more halogens; Or R
2and R
3together with the N atom connecting with them, form the heterocycloalkyl with 4 or 5 carbon atoms, described Heterocyclylalkyl is optionally replaced by the one or more substituting groups by being selected from halogen; Or low alkyl group; The low alkyl group being replaced by one or more halogens.
In one embodiment, formula I or IA compound are contained in the present invention, wherein, and R
1be selected from: low alkyl group; Cycloalkyl; Tetrahydropyran-4-base; Huo – NR
2r
3; And X Shi – (CH
2)
2; Yet R more particularly
1low alkyl group or cycloalkyl; Yet R more particularly
1it is low alkyl group.
In one embodiment, formula I or IA compound are contained in the present invention, wherein, and X Shi – (CH
2)
2.
In one embodiment, formula I or IA compound are contained in the present invention, and wherein Ar is phenyl.
In one embodiment, formula I or IA compound are contained in the present invention, wherein, and R
1be selected from: low alkyl group; Cycloalkyl; Tetrahydropyran-4-base; Huo – NR
2r
3; And Ar is phenyl; Yet R more particularly
1low alkyl group or cycloalkyl; Yet R more particularly
1it is low alkyl group.
In another particular of the present invention, described compound has according to the structure described in formula I or IA, thus R
1shi – NR
2r
3.
In another particular of the present invention, described compound has according to the structure described in formula I or IA, thus R
1shi – NR
2r
3; R
2hydrogen; And R
3low alkyl group; Tetrahydropyran-4-base;-CH
2-cycloalkyl; Or the cycloalkyl optionally being replaced by low alkyl group, described low alkyl group is replaced by one or more halogens.
In another particular of the present invention, described compound has according to the structure described in formula I or IA, thus R
1shi – NR
2r
3; And R
2and R
3together with the N atom connecting with them, form the heterocycloalkyl with 4 or 5 carbon atoms, described Heterocyclylalkyl is optionally replaced by the one or more substituting groups by being selected from halogen; Or the low alkyl group being replaced by one or more halogens.
In another particular of the present invention, described compound has according to the structure described in formula I or IA, wherein R
1that low alkyl group and Ar are phenyl.
In another particular of the present invention, described compound has according to the structure described in formula I or IA, wherein R
1it is low alkyl group; Ar is phenyl and X Shi – (CH
2)
2.
In a particular of the present invention, described compound has according to the structure described in formula I or IA, thus R
1shi – NR
2r
3; And Ar is phenyl.
In a particular of the present invention, described compound has the structure of formula I or IA, thus R
1shi – NR
2r
3; Ar is phenyl and R
2and R
3together with the N atom connecting with them, form the heterocycloalkyl with 4 or 5 carbon atoms, described Heterocyclylalkyl is optionally replaced by the one or more substituting groups by being selected from halogen; Or the low alkyl group being replaced by one or more halogens.
In a particular of the present invention, described compound has the structure of formula I or IA, thus R
1shi – NR
2r
3; X Shi – (CH
2)
2-and R
2and R
3together with the N atom connecting with them, form the heterocycloalkyl with 4 or 5 carbon atoms, described Heterocyclylalkyl is optionally replaced by the one or more substituting groups by being selected from halogen; Or the low alkyl group being replaced by one or more halogens.
In a particular of the present invention, described compound has the structure of formula I or IA, thus R
1shi – NR
2r
3; Ar is phenyl; R
2and R
3together with the N atom connecting with them, form the heterocycloalkyl with 4 or 5 carbon atoms, described Heterocyclylalkyl is optionally replaced by the one or more substituting groups by being selected from halogen; Or the low alkyl group being replaced by one or more halogens; And X Shi – (CH
2)
2.
In a particular, the present invention relates to following compound, purposes, medicament and method:
This compound is used for the treatment of and is characterized as some neurodegenerative illness of cytotoxic T AU malfolding and/or gathering to postpone or stop the progress of this type of disease.This type of disease is summarized as term tau pathology.Term " Tau pathology " refers to the disease of the toxicity that is characterized as dysfunction and/or TAU (it is characterized by oligomer, aggregate or the polymkeric substance of described albumen).This type of disease includes but not limited to that alzheimer's disease, pager's disease, corticobasal degeneration, stein-leventhal syndrome, frontotemporal dementia FTD and parkinsonism (are connected to karyomit(e) 17, FTDP-17).
The feature of Tau pathology is by insoluble aggregate or the polymkeric substance of the TAU of the hyperphosphorylation of the self-polymeric reaction formation of TAU monomer.It is not accurately known that TAU assembles related accurate molecular mechanism, but can relate to local sex change or the malfolding with TAU in self-organization (self-organise) conformation that extremely height of higher ordered structure is inclined to.Although can not get rid of at present this type of Abnormal Phosphorylation, be result rather than the reason of assembling, malfolding and gathering can be triggered by the hyperphosphorylation of TAU.
TAU be can in conjunction with and the therefore stable and albumen that defines micro-tubular structure and work in neurone.By the phosphorylation of TAU, regulate the combination of TAU and microtubule, and the phosphorylation state of control TAU also therefore regulates some TAU phosphorylation sites of TAU and microtubule binding affinity and kinases is identified accordingly.
The importance that TAU assembles is its relevant cytotoxicity, and this cytotoxicity has reduced neuronic integrity and functional and finally cause disease symptoms.By resolving familial in TAU, suddenly change, the direct effect of TAU in seizure of disease clearly established, and described sudden change shows it is to cause very morning and the sometimes reason of the tau pathology of invasive form.This type of sudden change comprises the change of the aminoacid sequence of the TAU that direct or indirect promotion neurotoxicity is assembled.
Alzheimer's disease (AD) is the most well known in these diseases, and in this disease, TAU is deposited in neurone with the form of neurofibrillary tangle (NFT).They are described first by Alois Alzheimer of the same name (one of his patient suffers from this illness).Term " alzheimer's disease " refers to and is characterized as neurodegenerative chronic progressive external sacred disease and most important (in early days) symptom is the loss of memory as used in this article.Along with disease progression, symptom can comprise confusion of consciousness, irritability and aggressive behaviour, anxious state of mind, language decline, long-term memory is lost and generally the giving up of patient (due to patient's sense organ decline).
Entanglement is by the albumen (being known as TAU) of microtubule-relevant
hyperphosphorylationform, cause that described albumen assembles with insoluble form.(these of the TAU of hyperphosphorylation are assembled also referred to as PHF or " conjugate spirals filament ").The accurate mechanism tangle forming is not understood completely, and whether tangle as causing the principal element of disease or playing a secondary role be that still tool is controversial.Due to the existence of senile plaque, AD is also classified as
amyloidosis.
Conventionally other symptom of observing neurofibrillary tangle comprises: stein-leventhal syndrome, dementia pugilistica (chronic trauma encephalopathic), be connected to frontotemporal dementia FTD and the parkinsonism of karyomit(e) 17, Lytico-Bodig sick (Guam type parkinsonian dementia syndrome), similar to AD but without spot, the leading dementia (tangle-predominant dementia with NFT) of entanglement with NFT of ganglioglioma and gangliocytoma, meningeal angiomatosis, subacute sclerosing panencephalitis, tuberous sclerosis, hallervorden-Spatz disease and lipofuscinosis.
The tau pathology of non-Alzheimer is classified as " Pick's syndrome " sometimes together.In Pick's disease and corticobasal degeneration, Protein tau is deposited in the neurone of swelling or " expanding as balloon " with the form of inclusion body.Argyrophilic grain sick (AGD), dull-witted another type, is in the micrography of cerebral tissue, to take that the argyrophilic grain that enriches and curling be mark.
As being described in WO2007/090617 at the described similar compound of formula IA of the present invention and I.
Compare with the discovery in WO2007/090617, found to exist removing (Clint) and lipophilicity to reduce significantly (during particularly the microsome outside human body is measured).It is very important for medicine, having appropriateness or low removing and lipophilicity, because this usually causes higher oral utilization ratio.Then reduce the removing of compound/medicine and lipophilicity can reduce potentially the required huge per daily dose of effect and thereby and obtain might as well be a lot of safety distribute (safety profile).Thereby low removing and lipophilicity are the essential features for the treatment of suitability.
The purposes of the following examples Table I compound below, the formula I that wherein these discoveries are emphasized and IA compound have caused having lower clearance rate (Clint) and lipotropy.
With carrier mediated system of distribution (CAMDIS) as described in EP1705474A1, lipophilicity data have been measured.
microsome stability Ce Shi – measures description
Microsome Stability Determination is measured the disappearance rate from the test compounds of hatching that contains human or animal's hepatomicrosome and metabolism cofactor (being generally NADPH).Measure and be mainly used to the metabolism tendency graduation of the relevant CYP mediation of the compound in chemical series (chemical series) and as the guidance of selecting for the sufficiently stable compound of pharmacokinetics and pharmacodynamic experiment.[except CYP, it is active also utilizing NADPH (such as flavones monooxygenase (flavone mono-oxygenases)) and those not need the microsome location enzyme of cofactor (such as Procaine esterase).]
In thering are the 96 hole depth orifice plates of finally hatching volume of 600 μ L, hatch.Hatch (finally) and contain 1-2 μ M test compounds, 0.5mg/mL liver particle (being people, rat or mouse conventionally) and NADPH regeneration system rapidly.After 1,3,6,9,15,25,35 and 45 minute, remove 50 μ L deciles and containing cancellation in interior target 150 μ L acetonitriles.Then before analyzing with LC-MS/MS, sample is cooling and centrifugal.
By the mapping of logarithm peak area ratio (test compounds peak area/interior mark peak area) contrast incubation time and be, under the initial rate that disappears of compound, data are carried out to linear fit at emphasis.Then use the slope of matching to calculate endogenous removing:
Cl
int(μ L/min/mg)=-slope (min-
1) * 1000/[protein concentration]
table I
From upper table, can find out, find particularly outside human body in microsome the remarkable increase of metabolic stability.
The new compound that the object of the invention is formula I and IA with and pharmacy acceptable salt, they for the purposes of the treatment of the relevant disease of the biological function with TAU imbalance (described disease comprise alzheimer's disease, pager's disease, corticobasal degeneration, stein-leventhal syndrome, frontotemporal dementia FTD and parkinsonism (being connected to karyomit(e) 17, FTDP-17)), their preparation and in the Control and prevention of disease based on according to the medicament of compound of the present invention.
Using the preferred indication of compound of the present invention is alzheimer's disease.
As used in this article, term " low alkyl group " represents the saturated straight or branched group that contains 1-7 carbon atom, for example, and methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, 2-butyl, the tertiary butyl etc.Preferred alkyl group is the group with 1-6 carbon atom.Preferred alkyl group is the group with 1-4 carbon atom.
As used in this article, term " low alkyl group being replaced by one or more halogens " represents alkyl group as defined above, and wherein at least one hydrogen atom is replaced by halogen, for example CF
3, CHF
2, CH
2f, CH
2cF
3, CH
2cH
2cF
3, CH
2cF
2cF
3deng.
Term " halogen " represents chlorine, iodine, fluorine and bromine.
Term " cycloalkyl " is the alkylene basic ring that contains 3-6 carboatomic ring atom.Preferably cyclopropyl or cyclohexyl.
Term " R
2and R
3together with the N atom connecting with them, form the heterocycloalkyl with 4 or 5 atoms " represent heterocyclic ring, wherein in 1-position, contain at least one N-atom, for example piperidin-1-yl or pyrrolidin-1-yl.
As used in this article, the group that term " lower alkoxy " represents alkyl residue wherein as defined above and described residue connects via Sauerstoffatom.
Term " pharmaceutically acceptable acid salt " comprises and has salt inorganic and that organic acid forms, all example hydrochloric acids, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, toxilic acid, acetic acid, succsinic acid, tartrate, methylsulfonic acid, tosic acid etc.
One embodiment of the invention are formula IA compounds, wherein X Shi – (CH
2)
2-, following compound for example
1-[3-(the fluoro-piperidin-1-yl of 4,4-bis-)-[1,2,4] thiadiazoles-5-yl]-4-[2-(4-methoxyl group-phenyl)-ethyl]-piperazine
1-[2-(the chloro-phenyl of 4-)-ethyl]-4-[3-(the fluoro-piperidin-1-yl of 4,4-bis-)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the chloro-phenyl of 4-)-ethyl]-4-[3-(the fluoro-pyrrolidin-1-yl of 3,3-bis-)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the chloro-phenyl of 4-)-ethyl]-4-[3-(4-fluoro-piperidine-1-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the chloro-phenyl of 4-)-ethyl]-4-[3-(4-trifluoromethyl-piperidin-1-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the chloro-phenyl of 4-)-ethyl]-4-(3-piperidin-1-yl-[1,2,4] thiadiazoles-5-yl)-piperazine
(5-{4-[2-(the chloro-phenyl of 4-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-cyclopropyl methyl-amine
(5-{4-[2-(the chloro-phenyl of 4-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-(tetrahydrochysene-pyrans-4-yl)-amine
(5-{4-[2-(the chloro-phenyl of 4-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-cyclohexyl-amine
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(the fluoro-piperidin-1-yl of 4,4-bis-)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(the fluoro-pyrrolidin-1-yl of 3,3-bis-)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(4-fluoro-piperidine-1-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(4-trifluoromethyl-piperidin-1-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-(3-pyrrolidin-1-yl-[1,2,4] thiadiazoles-5-yl)-piperazine
Cyclopropyl methyl-(5-{4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-amine
(5-{4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-(tetrahydrochysene-pyrans-4-yl)-amine
Cyclohexyl-(5-{4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-amine
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-(3-piperidin-1-yl-[1,2,4] thiadiazoles-5-yl)-piperazine
(5-{4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-(4-trifluoromethyl-cyclohexyl)-amine
Butyl-(5-{4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-ethyl-amine
1-(3-cyclohexyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(4-methoxyl group-phenyl)-ethyl]-piperazine
1-(3-cyclohexyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(3-methoxyl group-phenyl)-ethyl]-piperazine
1-(3-butyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(4-methoxyl group-phenyl)-ethyl]-piperazine
1-(3-cyclopropyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(4-methoxyl group-phenyl)-ethyl]-piperazine
1-(3-butyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(3-methoxyl group-phenyl)-ethyl]-piperazine
1-(3-cyclopropyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(3-methoxyl group-phenyl)-ethyl]-piperazine
1-[2-(the fluoro-phenyl of 4-)-ethyl]-4-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(4-methoxyl group-phenyl)-ethyl]-4-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(2-methoxyl group-pyridin-4-yl)-ethyl]-4-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
3-((3-chlorophenoxy) methyl)-5-(4-(3-anisole ethyl) piperazine-1-yl)-1,2,4-thiadiazoles
3-(2-(benzyloxy) ethyl)-5-(4-(3-anisole ethyl) piperazine-1-yl)-1,2,4-thiadiazoles
3-((4-fluorophenoxy) methyl)-5-(4-(3-anisole ethyl) piperazine-1-yl)-1,2,4-thiadiazoles
3-((4-fluorophenoxy) methyl)-5-(4-(4-anisole ethyl) piperazine-1-yl)-1,2,4-thiadiazoles or
5-(4-(4-anisole ethyl) piperazine-1-yl)-3-(trifluoromethyl)-1,2,4-thiadiazoles.
Another embodiment of the present invention is formula IA compound, wherein X Shi – (CH
2)
2and G
1be selected from: low alkyl group, cycloalkyl, tetrahydropyran-4-base; Benzyloxy-ethyl compound that the phenoxymethyl that halogen replaces, halogen replace, for example compound
1-(3-cyclohexyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(4-methoxyl group-phenyl)-ethyl]-piperazine
1-(3-cyclohexyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(3-methoxyl group-phenyl)-ethyl]-piperazine
1-(3-butyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(4-methoxyl group-phenyl)-ethyl]-piperazine
1-(3-cyclopropyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(4-methoxyl group-phenyl)-ethyl]-piperazine
1-(3-butyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(3-methoxyl group-phenyl)-ethyl]-piperazine
1-(3-cyclopropyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(3-methoxyl group-phenyl)-ethyl]-piperazine
1-[2-(the fluoro-phenyl of 4-)-ethyl]-4-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(4-methoxyl group-phenyl)-ethyl]-4-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(2-methoxyl group-pyridin-4-yl)-ethyl]-4-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
3-((3-chlorophenoxy) methyl)-5-(4-(3-anisole ethyl) piperazine-1-yl)-1,2,4-thiadiazoles
3-(2-(benzyloxy) ethyl)-5-(4-(3-anisole ethyl) piperazine-1-yl)-1,2,4-thiadiazoles
3-((4-chlorophenoxy) methyl)-5-(4-(3-anisole ethyl) piperazine-1-yl)-1,2,4-thiadiazoles or
3-((4-fluorophenoxy) methyl)-5-(4-(4-anisole ethyl) piperazine-1-yl)-1,2,4-thiadiazoles.
Other embodiments of the present invention are formula IA compounds, wherein X Shi – (CH
2)
2-and G
1shi – NR
2r
3.
Other embodiments of the present invention are formula IA compounds, wherein X Shi – (CH
2)
2-and G
1shi – NR
2r
3, R
2hydrogen, and R
3it is low alkyl group; Tetrahydropyran-4-base;-CH
2-cycloalkyl or the cycloalkyl optionally being replaced by low alkyl group, described low alkyl group is replaced by one or more halogens, for example compound
(5-{4-[2-(the chloro-phenyl of 4-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-cyclopropyl methyl-amine
(5-{4-[2-(the chloro-phenyl of 4-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-(tetrahydrochysene-pyrans-4-yl)-amine
(5-{4-[2-(the chloro-phenyl of 4-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-cyclohexyl-amine
Cyclopropyl methyl-(5-{4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-amine
(5-{4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-(tetrahydrochysene-pyrans-4-yl)-amine
Cyclohexyl-(5-{4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-amine or
(5-{4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-(4-trifluoromethyl-cyclohexyl)-amine
Other embodiments of the present invention are formula IA compounds, wherein X Shi – (CH
2)
2-and G
1shi – NR
2r
3, and R
2and R
3together with the N atom connecting with them, form the heterocycloalkyl with 4 or 5 carbon atoms, one or more substituting groups that described Heterocyclylalkyl is optionally selected from halogen or low alkyl group replace, described low alkyl group is replaced by one or more halogens, for example compound
1-[3-(the fluoro-piperidin-1-yl of 4,4-bis-)-[1,2,4] thiadiazoles-5-yl]-4-[2-(4-methoxyl group-phenyl)-ethyl]-piperazine
1-[2-(the chloro-phenyl of 4-)-ethyl]-4-[3-(the fluoro-piperidin-1-yl of 4,4-bis-)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the chloro-phenyl of 4-)-ethyl]-4-[3-(the fluoro-pyrrolidin-1-yl of 3,3-bis-)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the chloro-phenyl of 4-)-ethyl]-4-[3-(4-fluoro-piperidine-1-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the chloro-phenyl of 4-)-ethyl]-4-[3-(4-trifluoromethyl-piperidin-1-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the chloro-phenyl of 4-)-ethyl]-4-(3-piperidin-1-yl-[1,2,4] thiadiazoles-5-yl)-piperazine
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(the fluoro-piperidin-1-yl of 4,4-bis-)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(the fluoro-pyrrolidin-1-yl of 3,3-bis-)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(4-fluoro-piperidine-1-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(4-trifluoromethyl-piperidin-1-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-(3-pyrrolidin-1-yl-[1,2,4] thiadiazoles-5-yl)-piperazine
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-(3-piperidin-1-yl-[1,2,4] thiadiazoles-5-yl)-piperazine
Another embodiment of the present invention is the compound of formula IA, and wherein X is-CH
2-compound, compound 1-(2-methyl-benzyl)-4-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl for example]-piperazine or
3-(4-chlorobenzene ethyl)-5-(4-(2-methyl-benzyl) piperazine-1-yl)-1,2,4-thiadiazoles.
One embodiment of the invention are formula I compounds, wherein X Shi – (CH
2)
2-, following compound: 1-[3-(the fluoro-piperidin-1-yl of 4,4-bis-)-[1,2,4] thiadiazoles-5-yl for example]-4-[2-(4-methoxyl group-phenyl)-ethyl]-piperazine; 1-[2-(the chloro-phenyl of 4-)-ethyl]-4-[3-(the fluoro-piperidin-1-yl of 4,4-bis-)-[1,2,4] thiadiazoles-5-yl]-piperazine; 1-[2-(the chloro-phenyl of 4-)-ethyl]-4-[3-(the fluoro-pyrrolidin-1-yl of 3,3-bis-)-[1,2,4] thiadiazoles-5-yl]-piperazine; 1-[2-(the chloro-phenyl of 4-)-ethyl]-4-[3-(4-fluoro-piperidine-1-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine; 1-[2-(the chloro-phenyl of 4-)-ethyl]-4-[3-(4-trifluoromethyl-piperidin-1-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine; 1-[2-(the chloro-phenyl of 4-)-ethyl]-4-(3-piperidin-1-yl-[1,2,4] thiadiazoles-5-yl)-piperazine; (5-{4-[2-(the chloro-phenyl of 4-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-cyclopropyl methyl-amine; (5-{4-[2-(the chloro-phenyl of 4-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-(tetrahydrochysene-pyrans-4-yl)-amine; (5-{4-[2-(the chloro-phenyl of 4-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-cyclohexyl-amine; 1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(the fluoro-piperidin-1-yl of 4,4-bis-)-[1,2,4] thiadiazoles-5-yl]-piperazine; 1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(the fluoro-pyrrolidin-1-yl of 3,3-bis-)-[1,2,4] thiadiazoles-5-yl]-piperazine; 1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(4-fluoro-piperidine-1-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine; 1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(4-trifluoromethyl-piperidin-1-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine; 1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-(3-pyrrolidin-1-yl-[1,2,4] thiadiazoles-5-yl)-piperazine; Cyclopropyl methyl-(5-{4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-amine; (5-{4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-(tetrahydrochysene-pyrans-4-yl)-amine; Cyclohexyl-(5-{4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-amine; 1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-(3-piperidin-1-yl-[1,2,4] thiadiazoles-5-yl)-piperazine; (5-{4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-(4-trifluoromethyl-cyclohexyl)-amine; Butyl-(5-{4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-ethyl-amine; 1-(3-cyclohexyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(4-methoxyl group-phenyl)-ethyl]-piperazine; 1-(3-cyclohexyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(3-methoxyl group-phenyl)-ethyl]-piperazine; 1-(3-butyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(4-methoxyl group-phenyl)-ethyl]-piperazine; 1-(3-cyclopropyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(4-methoxyl group-phenyl)-ethyl]-piperazine; 1-(3-butyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(3-methoxyl group-phenyl)-ethyl]-piperazine; 1-(3-cyclopropyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(3-methoxyl group-phenyl)-ethyl]-piperazine; 1-[2-(the fluoro-phenyl of 4-)-ethyl]-4-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine; 1-[2-(4-methoxyl group-phenyl)-ethyl]-4-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine; 1-[2-(2-methoxyl group-pyridin-4-yl)-ethyl]-4-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine or 1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine.
Another embodiment of the present invention is formula I compound, wherein R
1low alkyl group, cycloalkyl or tetrahydrochysene-pyrans-4-base, following compound: 1-(3-cyclohexyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(4-methoxyl group-phenyl)-ethyl for example]-piperazine; 1-(3-cyclohexyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(3-methoxyl group-phenyl)-ethyl]-piperazine; 1-(3-butyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(4-methoxyl group-phenyl)-ethyl]-piperazine; 1-(3-cyclopropyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(4-methoxyl group-phenyl)-ethyl]-piperazine; 1-(3-butyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(3-methoxyl group-phenyl)-ethyl]-piperazine; 1-(3-cyclopropyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(3-methoxyl group-phenyl)-ethyl]-piperazine; 1-[2-(the fluoro-phenyl of 4-)-ethyl]-4-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine; 1-[2-(4-methoxyl group-phenyl)-ethyl]-4-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine; 1-[2-(2-methoxyl group-pyridin-4-yl)-ethyl]-4-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine; Or 1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine.
Other embodiments of the present invention are formula I compound, wherein R
2hydrogen and R
3low alkyl group, tetrahydropyran-4-base ,-CH
2-cycloalkyl or the cycloalkyl optionally being replaced by low alkyl group, described cycloalkyl is replaced by one or more halogens, following compound for example: (5-{4-[2-(the chloro-phenyl of 4-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-cyclopropyl methyl-amine; (5-{4-[2-(the chloro-phenyl of 4-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-(tetrahydrochysene-pyrans-4-yl)-amine; (5-{4-[2-(the chloro-phenyl of 4-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-cyclohexyl-amine; Cyclopropyl methyl-(5-{4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-amine; (5-{4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-(tetrahydrochysene-pyrans-4-yl)-amine; Cyclohexyl-(5-{4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-amine; Or (5-{4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-(4-trifluoromethyl-cyclohexyl)-amine
Other embodiments of the present invention are formula I compound, wherein R
2and R
3together with the N atom connecting with them, form the heterocycloalkyl with 4 or 5 carbon atoms, one or more substituting groups that described Heterocyclylalkyl is optionally selected from halogen or low alkyl group replace, described low alkyl group is replaced by one or more halogens, compound: 1-[3-(4 for example, the fluoro-piperidin-1-yl of 4-bis-)-[1,2,4] thiadiazoles-5-yl]-4-[2-(4-methoxyl group-phenyl)-ethyl]-piperazine; 1-[2-(the chloro-phenyl of 4-)-ethyl]-4-[3-(the fluoro-piperidin-1-yl of 4,4-bis-)-[1,2,4] thiadiazoles-5-yl]-piperazine; 1-[2-(the chloro-phenyl of 4-)-ethyl]-4-[3-(the fluoro-pyrrolidin-1-yl of 3,3-bis-)-[1,2,4] thiadiazoles-5-yl]-piperazine; 1-[2-(the chloro-phenyl of 4-)-ethyl]-4-[3-(4-fluoro-piperidine-1-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine; 1-[2-(the chloro-phenyl of 4-)-ethyl]-4-[3-(4-trifluoromethyl-piperidin-1-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine; 1-[2-(the chloro-phenyl of 4-)-ethyl]-4-(3-piperidin-1-yl-[1,2,4] thiadiazoles-5-yl)-piperazine; 1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(the fluoro-piperidin-1-yl of 4,4-bis-)-[1,2,4] thiadiazoles-5-yl]-piperazine; 1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(the fluoro-pyrrolidin-1-yl of 3,3-bis-)-[1,2,4] thiadiazoles-5-yl]-piperazine; 1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(4-fluoro-piperidine-1-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine; 1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(4-trifluoromethyl-piperidin-1-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine; 1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-(3-pyrrolidin-1-yl-[1,2,4] thiadiazoles-5-yl)-piperazine; Or 1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-(3-piperidin-1-yl-[1,2,4] thiadiazoles-5-yl)-piperazine
Other embodiments of the present invention are formula I compound, wherein R
2low alkyl group, following compound for example: butyl-(5-{4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-ethyl-amine.
This compound of formula IA or I and pharmacy acceptable salt thereof can be prepared by the method known in the art, and for example, by method as described below, the method comprises
By formula
Compound and formula
Compound coupling is to obtain formula
Wherein PG is that hydrogen or blocking group such as uncle-butoxy carbonyl (BOC), 9-fluorenylmethyloxycarbonyl (FMOC) etc. and hal are halogen such as chlorine, bromine, fluorine or iodine, and wherein definition as described above; If or need, the compound of acquisition is converted into pharmaceutically acceptable acid salt.In one embodiment, R
1have as to G
1defined same implication.
general experimental section
The preparation of formula IA of the present invention or I compound can be implemented by continuous or convergence type synthesis path.Synthesizing in following scheme of the compounds of this invention shows.The required technology of purifying of implementing reaction and products therefrom it is known to those skilled in the art that.Unless before having pointed out reverse situation, the substituting group and the index that use in the following description of method have given significance herein.More specifically, can be by method preparation given above, by given in an embodiment method or by similar method, preparation formula IA or I compound.Suitable reaction conditions for single reactions steps it is known to those skilled in the art that.In addition, for the reaction conditions of describing in the literature the reaction that impact describes referring to for example: Comprehensive Organic Transformations:A Guide to Functional Group Preparations, second edition, Richard C.Larock.John Wiley & Sons, New York, NY.1999).We find can conveniently implement reaction in solvent existence or non-existent situation.Character for the solvent using is without particular limitation, and precondition is that reaction to relating to or reagent have no adverse effect and the solvent that uses at least to a certain extent can solubilising reagent.The reaction of describing can occur under wide temperature range, and accurate temperature of reaction is not critical to the present invention.Can to the temperature range between refluxing, implement easily described reaction at-78 ℃.The time of reacting required also can the many factors of root Ju (it should be noted that the character of temperature of reaction and reagent) extensively change.Yet 0.5h will enough produce intermediate and the compound of describing conventionally to the period of several days.The order that reaction sequence is not limited to show in scheme, yet, according to parent material and corresponding reactivity thereof can be free change the order of reactions steps.Parent material be can commercially obtain or by with the following given similar method of method, by describe or embodiment in the method described in the reference quoted or prepare by methods known in the art.
scheme 1:
In one embodiment, R
1have as to G
1defined same implication.
A) amidine II can commercially obtain also and can synthesize according to method known in the art.These amidine derivatives II can be easily with there is base (NEt
3, DIPEA etc.) perchloromethyl mercaptan react to provide chloro-thiadiazoles derivative III.
B) chloro-thiadiazoles derivative III easily with the bridged piperazine derivatives replacing react directly to obtain final thiadiazoles derivative I or alternatively III react to provide thiadiazoles derivative IV with the piperazine (PG=Boc etc.) of protection.
C) IV go protection to be to carry out under applicable condition, at PG=Boc in acidic conditions in the situation that, to produce free bridged piperazine derivatives, described bridged piperazine derivatives easily be applicable to electrophile (such as hal-X-Ar-(R
4)
n) react to obtain final thiadiazoles derivative I.
scheme 2:
D) the bromo-5-of 3-is chloro-1,2, and 4-thiadiazoles and 3,5-bis-are chloro-1,2, and 4-thiadiazoles V can commercially obtain and can react to produce thiadiazoles derivative VI or IX with (PG=Boc etc.) of protection or the piperazine replacing easily.
E) thiadiazoles derivative VI or IX and applicable amine react easily to produce final derivative I the IX in the situation that or produce the thiadiazoles derivative VII of protection at VI in the situation that.
F) VII go protection to be to carry out under applicable condition, at PG=Boc in acidic conditions in the situation that, to produce free bridged piperazine derivatives, described bridged piperazine derivatives easily be applicable to electrophile (such as hal-X-Ar-(R
4)
n) react to obtain final thiadiazoles derivative I.
experimental section
abbreviation:
DCM=methylene dichloride;
DIPEA=N, N-diisopropylethylamine;
EtOH=ethanol;
Et
3n=triethylamine; ;
HPLC=high pressure lipuid chromatography (HPLC);
Exemplary compounds of the present invention is listed in Table II
table 2.
Embodiment 1
1-[3-(the fluoro-piperidin-1-yl of 4,4-bis-)-[1,2,4] thiadiazoles-5-yl]-4-[2-(4-methoxyl group-phenyl)-ethyl]-piperazine
a) 1-(3-bromo-[1,2,4] thiadiazoles-5-yl)-4-[2-(4-methoxyl group-phenyl)-ethyl]-piperazine
By the bromo-5-of 3-chloro-1,2,4-thiadiazoles (300mg, 1.5mmol), 1-(4-anisole ethyl) piperazine dihydrochloride (485mg, 1.65mmol) and DIPEA (641mg, 867 μ L, 4.96mmol) mixture in EtOH (10mL) stirs and spends the night at ambient temperature.By mixture vacuum concentration, by silica gel column chromatography, use heptane and ethyl acetate to carry out gradient elution residue and carry out purifying, to produce the title compound that is pale solid of 489mg (85%) after the cut evaporation containing product.MS(m/e)：383.2(MH
+)。
b) 1-[3-(the fluoro-piperidin-1-yl of 4,4-bis-)-[1,2,4] thiadiazoles-5-yl]-4-[2-(4-methoxyl group-
phenyl)-ethyl]-piperazine
By the bromo-5-of 3-(4-(4-anisole ethyl) piperazine-1-yl)-1,2,4-thiadiazoles (55mg, 143 μ mol), 4,4-difluoro piperidine hydrochlorate (67.8mg, 430 μ mol) and mixture 200 ℃ at the microwave heating 2.5h of DIPEA (185mg, 251 μ l, 1.43mmol) in METHYLPYRROLIDONE (1mL).By preparative reversed-phase HPLC, use from acetonitrile, water and NEt
3the gradient forming is carried out wash-out and is carried out the amber reaction soln of purifying, produces the title compound that is pale solid of 41.8mg (69%) after the cut evaporation that contains product.MS(m/e):424.2(MH
+)。
Embodiment 2
1-[2-(the chloro-phenyl of 4-)-ethyl]-4-[3-(the fluoro-piperidin-1-yl of 4,4-bis-)-[1,2,4] thiadiazoles-5-yl]-piperazine
a) 1-(3-bromo-[1,2,4] thiadiazoles-5-yl)-4-[2-(the chloro-phenyl of 4-)-ethyl]-piperazine
With for 1-, (3-bromo-[1,2,4] thiadiazoles-5-yl)-4-[2-(4-methoxyl group-phenyl)-ethyl] (embodiment 1 for-piperazine, step synthetic described operation a) is similar, title compound is from the bromo-5-of 3-chloro-1 as white solid, the preparation of 2,4-thiadiazoles and 1-(4-chlorobenzene ethyl) piperazine dihydrochloride.MS(m/e):389.1(MH
+)。
b) 1-[2-(the chloro-phenyl of 4-)-ethyl]-4-[3-(the fluoro-piperidin-1-yl of 4,4-bis-)-[1,2,4] thiadiazoles
-5-yl]-piperazine
With for 1-[3-(4, the fluoro-piperidin-1-yl of 4-bis-)-[1,2,4] thiadiazoles-5-yl]-4-[2-(4-methoxyl group-phenyl)-ethyl] (embodiment 1 for-piperazine, step b) synthetic described operation is similar, and title compound is that (3-bromo-[1,2 from 1-, 4] thiadiazoles-5-yl)-4-[2-(the chloro-phenyl of 4-)-ethyl]-piperazine and the preparation of 4,4-difluoro piperidine hydrochlorate.MS(m/e):428.3(MH
+)。
Embodiment 3
1-[2-(the chloro-phenyl of 4-)-ethyl]-4-[3-(the fluoro-pyrrolidin-1-yl of 3,3-bis-)-[1,2,4] thiadiazoles-5-
Base]-piperazine
With for 1-[3-(4, the fluoro-piperidin-1-yl of 4-bis-)-[1,2,4] thiadiazoles-5-yl]-4-[2-(4-methoxyl group-phenyl)-ethyl] (embodiment 1 for-piperazine, step b) synthetic described operation is similar, and title compound is that (3-bromo-[1,2 from 1-, 4] thiadiazoles-5-yl)-4-[2-(the chloro-phenyl of 4-)-ethyl]-piperazine and the preparation of 3,3-difluoro pyrrolidine hydrochloride.MS(m/e):414.3(MH
+)。
Embodiment 4
1-[2-(the chloro-phenyl of 4-)-ethyl]-4-[3-(4-fluoro-piperidine-1-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
With for 1-[3-(4, the fluoro-piperidin-1-yl of 4-bis-)-[1,2,4] thiadiazoles-5-yl]-4-[2-(4-methoxyl group-phenyl)-ethyl] (embodiment 1 for-piperazine, step b) synthetic described operation is similar, title compound is from 1-(3-bromo-[1,2,4] thiadiazoles-5-yl)-4-[2-(the chloro-phenyl of 4-)-ethyl]-piperazine and the preparation of 4-fluorine piperidine hydrochlorate.MS(m/e):410.2(MH
+)。
Embodiment 5
1-[2-(the chloro-phenyl of 4-)-ethyl]-4-[3-(4-trifluoromethyl-piperidin-1-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
With for 1-[3-(4, the fluoro-piperidin-1-yl of 4-bis-)-[1,2,4] thiadiazoles-5-yl]-4-[2-(4-methoxyl group-phenyl)-ethyl] (embodiment 1 for-piperazine, step b) synthetic described operation is similar, title compound is from 1-(3-bromo-[1,2,4] thiadiazoles-5-yl)-4-[2-(the chloro-phenyl of 4-)-ethyl]-piperazine and the preparation of 4-(trifluoromethyl) piperidine hydrochlorate.MS(m/e):460.2(MH
+)。
Embodiment 6
1-[2-(the chloro-phenyl of 4-)-ethyl]-4-(3-piperidin-1-yl-[1,2,4] thiadiazoles-5-yl)-piperazine
With for 1-[3-(4, the fluoro-piperidin-1-yl of 4-bis-)-[1,2,4] thiadiazoles-5-yl]-4-[2-(4-methoxyl group-phenyl)-ethyl] (embodiment 1 for-piperazine, step b) synthetic described operation is similar, title compound is from 1-(3-bromo-[1,2,4] thiadiazoles-5-yl)-4-[2-(the chloro-phenyl of 4-)-ethyl]-piperazine and piperidines preparation.MS(m/e):392.2(MH
+)。
Embodiment 7
(5-{4-[2-(the chloro-phenyl of 4-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-cyclopropyl methyl-amine
With for 1-[3-(4, the fluoro-piperidin-1-yl of 4-bis-)-[1,2,4] thiadiazoles-5-yl]-4-[2-(4-methoxyl group-phenyl)-ethyl] (embodiment 1 for-piperazine, step b) synthetic described operation is similar, title compound is from 1-(3-bromo-[1,2,4] thiadiazoles-5-yl)-4-[2-(the chloro-phenyl of 4-)-ethyl]-piperazine and cyclopropyl-methylamine preparation.MS(m/e):378.3(MH
+)。
Embodiment 8
(5-{4-[2-(the chloro-phenyl of 4-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-(tetrahydrochysene-pyrans-4-yl)-amine
With for 1-[3-(4, the fluoro-piperidin-1-yl of 4-bis-)-[1,2,4] thiadiazoles-5-yl]-4-[2-(4-methoxyl group-phenyl)-ethyl] (embodiment 1 for-piperazine, step b) synthetic described operation is similar, title compound is from 1-(3-bromo-[1,2,4] thiadiazoles-5-yl)-4-[2-(the chloro-phenyl of 4-)-ethyl]-piperazine and the preparation of tetrahydrochysene-2H-pyrans-4-amine.MS(m/e):408.3(MH
+)。
Embodiment 9
(5-{4-[2-(the chloro-phenyl of 4-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-cyclohexyl-amine
With for 1-[3-(4, the fluoro-piperidin-1-yl of 4-bis-)-[1,2,4] thiadiazoles-5-yl]-4-[2-(4-methoxyl group-phenyl)-ethyl] (embodiment 1 for-piperazine, step b) synthetic described operation is similar, title compound is from 1-(3-bromo-[1,2,4] thiadiazoles-5-yl)-4-[2-(the chloro-phenyl of 4-)-ethyl]-piperazine and encircle amine preparation.MS(m/e):406.4(MH
+)。
Embodiment 10
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(the fluoro-piperidin-1-yl of 4,4-bis-)-[1,2,4] thiadiazoles-5-yl]-piperazine
a) 1-(3-bromo-[1,2,4] thiadiazoles-5-yl)-4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine
With for 1-, (3-bromo-[1,2,4] thiadiazoles-5-yl)-4-[2-(4-methoxyl group-phenyl)-ethyl] (embodiment 1 for-piperazine, step synthetic described operation a) is similar, title compound is from the bromo-5-of 3-chloro-1 as colourless thickness oily matter, the preparation of 2,4-thiadiazoles and 1-(3,4-difluorobenzene ethyl) piperazine dihydrochloride.MS(m/e):391.2(MH
+)。
b) 1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(the fluoro-piperidin-1-yl of 4,4-bis-)-[1,2,4] thiophene
diazole-5-yl]-piperazine
With for 1-[3-(4, the fluoro-piperidin-1-yl of 4-bis-)-[1,2,4] thiadiazoles-5-yl]-4-[2-(4-methoxyl group-phenyl)-ethyl] the synthetic described operation of-piperazine (embodiment 1, step b) is similar, and title compound is that (3-bromo-[1 from 1-, 2,4] thiadiazoles-5-yl)-4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine and the preparation of 4,4-difluoro piperidine hydrochlorate.MS(m/e):430.3(MH
+)。
Embodiment 11
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(the fluoro-pyrrolidin-1-yl of 3,3-bis-)-[1,2,4] thiadiazoles-5-yl]-piperazine
With for 1-[3-(4, the fluoro-piperidin-1-yl of 4-bis-)-[1,2,4] thiadiazoles-5-yl]-4-[2-(4-methoxyl group-phenyl)-ethyl] the synthetic described operation of-piperazine (embodiment 1, step b) is similar, and title compound is that (3-bromo-[1 from 1-, 2,4] thiadiazoles-5-yl)-4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine and the preparation of 3,3-difluoro pyrrolidine hydrochloride.MS(m/e):416.3(MH
+)。
Embodiment 12
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(4-fluoro-piperidine-1-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
With for 1-[3-(4, the fluoro-piperidin-1-yl of 4-bis-)-[1,2,4] thiadiazoles-5-yl]-4-[2-(4-methoxyl group-phenyl)-ethyl] (embodiment 1 for-piperazine, step b) synthetic described operation is similar, and title compound is that (3-bromo-[1,2 from 1-, 4] thiadiazoles-5-yl)-4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine and the preparation of 4-fluorine piperidine hydrochlorate.MS(m/e):412.3(MH
+)。
Embodiment 13
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(4-trifluoromethyl-piperidin-1-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
With for 1-[3-(4, the fluoro-piperidin-1-yl of 4-bis-)-[1,2,4] thiadiazoles-5-yl]-4-[2-(4-methoxyl group-phenyl)-ethyl] (embodiment 1 for-piperazine, step b) synthetic described operation is similar, and title compound is that (3-bromo-[1,2 from 1-, 4] thiadiazoles-5-yl)-4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine and the preparation of 4-(trifluoromethyl) piperidine hydrochlorate.MS(m/e):462.3(MH
+)。
Embodiment 14
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-(3-pyrrolidin-1-yl-[1,2,4] thiadiazoles-5-yl)-piperazine
With for 1-[3-(4, the fluoro-piperidin-1-yl of 4-bis-)-[1,2,4] thiadiazoles-5-yl]-4-[2-(4-methoxyl group-phenyl)-ethyl] (embodiment 1 for-piperazine, step b) synthetic described operation is similar, and title compound is that (3-bromo-[1,2 from 1-, 4] thiadiazoles-5-yl)-4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine and tetramethyleneimine preparation.MS(m/e):380.3(MH
+)。
Embodiment 15
Cyclopropyl methyl-(5-{4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-amine
With for 1-[3-(4, the fluoro-piperidin-1-yl of 4-bis-)-[1,2,4] thiadiazoles-5-yl]-4-[2-(4-methoxyl group-phenyl)-ethyl] (embodiment 1 for-piperazine, step b) synthetic described operation is similar, and title compound is that (3-bromo-[1,2 from 1-, 4] thiadiazoles-5-yl)-4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine and cyclopropyl-methylamine preparation.MS(m/e):380.3(MH
+)。
Embodiment 16
(5-{4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-(tetrahydrochysene-pyrans-4-yl)-amine
With for 1-[3-(4, the fluoro-piperidin-1-yl of 4-bis-)-[1,2,4] thiadiazoles-5-yl]-4-[2-(4-methoxyl group-phenyl)-ethyl] (embodiment 1 for-piperazine, step b) synthetic described operation is similar, and title compound is that (3-bromo-[1,2 from 1-, 4] thiadiazoles-5-yl)-4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine and the preparation of tetrahydrochysene-2H-pyrans-4-amine.MS(m/e):410.3(MH
+)。
Embodiment 17
Cyclohexyl-(5-{4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-amine
With for 1-[3-(4, the fluoro-piperidin-1-yl of 4-bis-)-[1,2,4] thiadiazoles-5-yl]-4-[2-(4-methoxyl group-phenyl)-ethyl] (embodiment 1 for-piperazine, step b) synthetic described operation is similar, and title compound is that (3-bromo-[1,2 from 1-, 4] thiadiazoles-5-yl)-4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine and hexahydroaniline preparation.MS(m/e):408.4(MH
+)。
Embodiment 18
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-(3-piperidin-1-yl-[1,2,4] thiadiazoles-5-yl)-piperazine
With for 1-[3-(4, the fluoro-piperidin-1-yl of 4-bis-)-[1,2,4] thiadiazoles-5-yl]-4-[2-(4-methoxyl group-phenyl)-ethyl] (embodiment 1 for-piperazine, step b) synthetic described operation is similar, and title compound is that (3-bromo-[1,2 from 1-, 4] thiadiazoles-5-yl)-4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine and the preparation of piperidines alkane.MS(m/e):394.2(MH
+)。
Embodiment 19
(5-{4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-(4-trifluoromethyl-cyclohexyl)-amine
With for 1-[3-(4, the fluoro-piperidin-1-yl of 4-bis-)-[1,2,4] thiadiazoles-5-yl]-4-[2-(4-methoxyl group-phenyl)-ethyl] (embodiment 1 for-piperazine, step b) synthetic described operation is similar, and title compound is that (3-bromo-[1,2 from 1-, 4] thiadiazoles-5-yl)-4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine and the preparation of 4-(trifluoromethyl) hexahydroaniline.MS(m/e):476.2(MH
+)。
Embodiment 20
Butyl-(5-{4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-ethyl-amine
With for 1-[3-(4, the fluoro-piperidin-1-yl of 4-bis-)-[1,2,4] thiadiazoles-5-yl]-4-[2-(4-methoxyl group-phenyl)-ethyl] (embodiment 1 for-piperazine, step b) synthetic described operation is similar, and title compound is that (3-bromo-[1,2 from 1-, 4] thiadiazoles-5-yl)-4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine and the preparation of N-ethyl fourth-1-amine.MS(m/e):410.3(MH
+)。
Embodiment 21
1-(3-cyclohexyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(4-methoxyl group-phenyl)-ethyl]-piperazine
a) the chloro-3-cyclohexyl of 5--[1,2,4] thiadiazoles
Hexanaphthene carbonamidine (100mg, 792 μ mol) and DIPEA (512mg, 3.96mmol) are processed with perchloro-methyl mercaptan (147mg, 792 μ mol) at 0-5 ℃ in 10mL DCM in 5mL DCM, and stirred 1hr at 0-5 ℃.By mixture vacuum concentration, to obtain brown solid, described solid does not need to be just further purified and can use in step subsequently.
b) 1-(3-cyclohexyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(4-methoxyl group-phenyl)-ethyl]-
piperazine
By the chloro-3-of 5-cyclohexyl-1,2,4-thiadiazoles (32.0mg, 158 μ mol), 1-(4-anisole ethyl) piperazine dihydrochloride (51.0mg, 174 μ mol) and the mixture of DIPEA in EtOH are at 90 ℃ of oil bath heating 30min.By this mixture by preparative acetonitrile, water and NEt for reversed-phase HPLC
3the gradient forming comes wash-out to carry out purifying, to produce the title compound that 13.7mg (22%) is light brown solid after the cut evaporation containing product.MS(m/e):387.3(MH
+)。
Embodiment 22
1-(3-cyclohexyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(3-methoxyl group-phenyl)-ethyl]-piperazine
With for 1-(3-cyclohexyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(4-methoxyl group-phenyl)-ethyl] (embodiment 21 for-piperazine, step b) synthetic described operation is similar, title compound is from the chloro-3-cyclohexyl-[1 of 5-as light brown solid, 2,4] thiadiazoles and 1-(3-anisole ethyl) piperazine dihydrochloride preparation.MS(m/e)：387.3(MH
+)。
Embodiment 23
1-(3-butyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(4-methoxyl group-phenyl)-ethyl]-piperazine
With for 1-(3-cyclohexyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(4-methoxyl group-phenyl)-ethyl] (embodiment 21 for-piperazine, step b) synthetic described operation is similar, title compound is from uncle 3--5-chloro-[1,2,4] thiadiazoles and 1-(4-anisole ethyl) piperazine dihydrochloride preparation.MS(m/e):361.3(MH
+)。
Embodiment 24
1-(3-cyclopropyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(4-methoxyl group-phenyl)-ethyl]-piperazine
With for 1-(3-cyclohexyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(4-methoxyl group-phenyl)-ethyl] (embodiment 21 for-piperazine, step b) synthetic described operation is similar, title compound is from the chloro-3-cyclopropyl-[1 of 5-, 2,4] thiadiazoles and 1-(4-anisole ethyl) piperazine dihydrochloride preparation.MS(m/e):345.2(MH
+)。
Embodiment 25
1-(3-butyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(3-methoxyl group-phenyl)-ethyl]-piperazine
With for 1-(3-cyclohexyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(4-methoxyl group-phenyl)-ethyl] (embodiment 21 for-piperazine, step b) synthetic described operation is similar, title compound is from uncle 3--5-chloro-[1,2,4] thiadiazoles and 1-(3-anisole ethyl) piperazine dihydrochloride preparation.MS(m/e):361.3(MH
+)。
Embodiment 26
1-(3-cyclopropyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(3-methoxyl group-phenyl)-ethyl]-piperazine
With for 1-(3-cyclohexyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(4-methoxyl group-phenyl)-ethyl] (embodiment 21 for-piperazine, step b) synthetic described operation is similar, title compound is from the chloro-3-cyclopropyl-[1 of 5-, 2,4] thiadiazoles and 1-(3-anisole ethyl) piperazine dihydrochloride preparation.MS(m/e)：MS(m/e):345.2(MH
+)。
Embodiment 27
1-[2-(the fluoro-phenyl of 4-)-ethyl]-4-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
With for 1-(3-cyclohexyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(4-methoxyl group-phenyl)-ethyl] (embodiment 21 for-piperazine, step b) synthetic described operation is similar, title compound is from the chloro-3-of 5-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles and 1-(4-fluorobenzene ethyl) piperazine dihydrochloride preparation.MS(m/e)：377.3(MH
+)。
Embodiment 28
1-[2-(4-methoxyl group-phenyl)-ethyl]-4-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
With for 1-(3-cyclohexyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(4-methoxyl group-phenyl)-ethyl] (embodiment 21 for-piperazine, step b) synthetic described operation is similar, title compound is from the chloro-3-of 5-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles and 1-(4-anisole ethyl) piperazine dihydrochloride preparation.MS(m/e)：389.3(MH
+)。
Embodiment 29
1-[2-(2-methoxyl group-pyridin-4-yl)-ethyl]-4-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
With for 1-(3-cyclohexyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(4-methoxyl group-phenyl)-ethyl] (embodiment 21 for-piperazine, step b) synthetic described operation is similar, title compound is from the chloro-3-of 5-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles and 1-(2-(2-methoxypyridine-4-yl) ethyl) piperazine trihydrochloride salt preparation.MS(m/e)：390.3(MH
+)。
Embodiment 30
1-(2-methyl-benzyl)-4-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
a) 1-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
By the chloro-3-of 5-(tetrahydrochysene-2H-pyrans-4-yl)-1,2,4-thiadiazoles (2.1g, 10.3mmol) and piperazine (8.84g, the 103mmol) mixture in EtOH (50mL) is at stirring at room and vacuum concentration.By silicon-dioxide column chromatography, use from DCM, methyl alcohol and NH
3the gradient elution forming carrys out purifying residue, to produce the title compound that 2.48g (95%) is light brown solid after the cut evaporation containing product.MS(m/e)：255.1(MH
+)。
b) 1-(2-methyl-benzyl)-4-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
piperazine
By 5-(piperazine-1-yl)-3-(tetrahydrochysene-2H-pyrans-4-yl)-1,2,4-thiadiazoles (19.1mg, 75.0 μ mol), 1-(chloromethyl)-2-methylbenzene (31.6mg, 225 μ mol) and DIPEA (96.9mg, 131 μ L, 750 μ mol) mixture in METHYLPYRROLIDONE (1mL) under microwave exposure at 180 ℃ of heating 10min.By preparative reversed-phase HPLC, use from acetonitrile, water and NEt
3the gradient elution forming carrys out purifying gained reaction soln, to produce 13mg (48%) title compound after the cut evaporation containing product.MS(m/e)：359.2(MH+)。
Embodiment 31
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
With for 1-(2-methyl-benzyl)-4-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl] (embodiment 30 for-piperazine, step b) synthetic described operation is similar, title compound is from 1-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine and 4-(2-bromotrifluoromethane)-1, the preparation of 2-difluorobenzene.MS(m/e):395.2(MH+)。
Embodiment 37
5-(4-(4-anisole ethyl) piperazine-1-yl)-3-(trifluoromethyl)-1,2,4-thiadiazoles
With for 1-(2-methyl-benzyl)-4-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl] (embodiment 30 for-piperazine, step b) synthetic described operation is similar, title compound is from 5-(piperazine-1-yl)-3-(trifluoromethyl)-1,2,4-thiadiazoles and 1-(2-bromotrifluoromethane)-4-anisole preparation.
the structure of TAU gene overexpression clone
By the cDNA subclone to coding mankind's TAU-P301L albumen (wherein the proline(Pro) in 301 positions is replaced by leucine residue), TAU expression plasmid is fabricated to Mammalia Vector pcDNA3.1, produces plasmid pcDNA3.1-TAUP301L.Use lipofectamine reagent by plasmid pcDNA3.1 and pcDNA3.1-TAU P301L transfection to human nerve cell oncocyte (BE-M17; ATCC No.CRL-2267
tM) in and by antibiotics resistance, select (Geneticin (G418)) to select plasmid stable integration to the independently cloned cell line in genome subsequently, produce clone M17.pcDNA3 and M17_3TAUP301L.By western blot analysis, confirm
the expression of the TAUP301L gene in cell.
tAU express cell is as the purposes of neuronal degeneration model
Behind 7 days of cytodifferentiation of using vitamin A acid (RA), find that the expression of TAU P301L in M17_3TAU (P301L) cell is expressed with respect to the control cells without TAU, it has given the toxicity increasing.With the differentiation of the cell of RA, produce the gathering of phosphorylation and TAU subsequently, the tau pathology of promotion in these cells.By the level of serum lactic dehydrogenase (LDH) quantitatively being measured to the cytotoxicity of cell.In dead cell, because the LDH that loses of membrane integrity spills and enters in substratum from cell.
In brief, before 3 days of experiment, prepare the preculture of M17.pcDNA3 and M17_3TAU (P301L) cell, from storing cultivation (stock culture), detecting density in substratum is that 50.000-100.000 cell/cm2 is (without phenol red (Gibco, Cat.31985-047) Optimem that is supplemented with 1% foetal calf serum (FCS), 1mM Sodium.alpha.-ketopropionate, 1 * non-essential amino acid (NEAA), 500 μ g/ml G418 and 0,5 * microbiotic/antifungal (ABAM) simplifies serum).On the same day of experiment, these precultures be diluted to～0,1.106 cell/ml and 60 these suspension of μ L in the detection substratum without FCS are dispersed in 96 hole microtiter plates by every hole.At 37 ℃/5%CO2, hatch after 3 hours, the isopyknic detection substratum that contains 2.5 μ M RA is added and subsequently at 37 ℃/5%CO
2hatch 7 days.After 7 days, according to the operation instruction of manufacturers, use Promega Cytotox96 on-radiation cytotoxic assay (Cat.G1780) to determine that LDH is active.Cytotoxicity is measured as the increase of LDH in supernatant liquor divided by the ratio of the increase of LDH in total cell suspending liquid (summation of the LDH measuring in cell and supernatant liquor).Fig. 1 demonstration is compared with M17.pcDNA3 cell, by the toxicity of M17_3TAU (P301L) cytodifferentiation after 7 days of vitamin A acid.It is existed the obvious higher proof of toxicity in M17_3TAU (P301L) cell and is caused by TAU P301 protein mutant especially.
the purposes of the neurocytoma tau pathology model of SCREENED COMPOUND
The activity that M17_3TAU (P301L) clone makes assessment suppress the Cytotoxic novel cpd of TAU-induction becomes possibility.Find the activity inhibitor of the Tau pathology in these cells, in the substratum of M17_3TAU (P301L) cell, (described in above embodiment, processed) increase that suppresses cytotoxicity or LDH.The ability of the toxicity that under test different concns, (scope of the paramount effective concentration of low invalid concentration) compound obstruction TAU-brings out.Then, their EC of inhibitor curve calculation that using dosage relies on
50(Table III).
Although disclosed compound pharmacological characteristics changes with structural modification in this invention, active compound has the EC in the scope of approximately 0.0005 to 1.0 μ M in the mensuration based on cell the most especially
50.
The compound of test shows as the EC50 value (μ M) as shown in Table III.
table III
| Embodiment | EC 50(μM) | Embodiment | EC 50(μM) |
| 1 | 0.0006 | 17 | 0.0038 |
| 2 | 0.0536 | 18 | 0.0464 |
| 3 | 0.0088 | 19 | 0.3403 |
| 4 | 0.0846 | 20 | 0.7088 |
| 5 | 0.047 | 21 | 0.0022 |
| 6 | 0.0641 | 22 | 0.003 |
| 7 | 0.0172 | 23 | 0.0005 |
| 8 | 0.0522 | 24 | 0.0445 |
| 9 | 0.0094 | 25 | 0.0022 |
| 10 | 0.0121 | 26 | 0.4102 |
| 11 | 0.0114 | 27 | 0.3088 |
| 12 | 0.0333 | 28 | 0.0333 |
| 13 | 0.0153 | 29 | 0.2027 |
| 14 | 0.1757 | 30 | 0.4135 |
| 15 | 0.0384 | 31 | 0.3085 |
| 16 | 0.0345 | ? | ? |
The pharmacy acceptable salt of formula IA or I compound agent and formula IA or I compound can be used as medicament, as the form with pharmaceutical preparation.Can oral administration of pharmaceutical preparations, as the form with tablet, coated tablet, drageeing, hard or soft gelatinum capsule, solution, emulsion or suspension.Yet, use also and can be realized by rectum (as the form with suppository) or parenteral (as the form with solution).
Formula IA or I compound can be processed with the inorganic or organic carrier of the pharmaceutically inertia of useful in preparing drug formulations.Lactose, W-Gum or derivatives thereof, talcum, stearic acid or its salt etc. can be used, for example, and as the examples of such carriers for tablet, coated tablet, drageeing and hard gelatinum capsule.For the applicable carrier of soft gelatinum capsule, be, for example, vegetables oil, wax, fat, semisolid and liquid polyol etc.Yet according to the character of active substance, conventionally the in the situation that of soft gelatinum capsule, do not need carrier.The applicable carrier of preparing for solution and syrup is, for example, and water, polyvalent alcohol, glycerine, plant wet goods.For the applicable carrier of suppository, be, for example, natural or winterized stearin, wax, fat, semiliquid or liquid polyol etc.
In addition, pharmaceutical preparation can contain sanitas, solubilizing agent, stablizer, wetting agent, emulsifying agent, sweetener, tinting material, correctives, for changing salt, buffer reagent, sequestering agent or the antioxidant of osmotic pressure.They also contain other therapeutically valuable material.
Contain formula IA or I compound or its pharmacy acceptable salt and the therapeutically medicament of inert support and their preparation method, also be object of the present invention, described preparation method comprise the compound of one or more formulas IA or I and/or pharmaceutically acceptable acid salt and, if needed, one or more other therapeutically valuable material therapeutically together with inert support, be combined into galenic administration form with one or more.
According to the present invention, most preferred indication is those, it comprises the illness of central nervous system, for example alzheimer's disease, pager's disease, corticobasal degeneration, stein-leventhal syndrome, frontotemporal dementia FTD and parkinsonism (are connected to karyomit(e) 17, treatment FTDP-17) or prevention.
Dosage can change in wide in range restriction and wish (will), certainly in each specific situation, must regulate dosage to adapt to individual demand.Orally administered in the situation that, adult's dosage can be at its pharmacy acceptable salt of compound of Formula I or respective amount every day about 0.01mg to changing between about 1000mg.Per daily dose can be used as single dose or is applied as fractionated dose, in addition, when finding suggestion to use the dosage that surpasses the upper limit, also can surpass the upper limit.
Tablet formulation (wet granulation)
preparation section
1. article 1,2,3 and 4 are mixed and granulated by purified water.
Granule is dry at 50 ℃ 2..
3. granule is passed through to applicable milling apparatus.
4. article 5 added and mix three minutes; On applicable tabletting machine, suppress.
Capsule preparations
preparation section
1. article 1,2 and 3 are mixed 30 minutes in applicable mixing tank.
2. article 4 and 5 added and mix 3 minutes.
3. be filled in applicable capsule.
Claims (15)
1. formula IA compound or its active salt pharmaceutically, its relate to comprise the single diastereomer of formula (I) compound or the stereoisomeric forms in any ratio of enantiomorph with and racemize or non-racemic mixture;
Wherein
G
1it is low alkyl group; The low alkyl group being replaced by one or more halogens; Cycloalkyl; Tetrahydropyran-4-base; Styroyl; The styroyl being replaced by one or more halogens; Phenoxymethyl; The phenoxymethyl being replaced by one or more halogens; Benzyloxy-ethyl; Benzyloxy-the ethyl being replaced by one or more halogens; Huo Shi – NR
2r
3;
R
2hydrogen or low alkyl group;
R
3low alkyl group, tetrahydropyran-4-base-CH
2-cycloalkyl or the cycloalkyl optionally being replaced by low alkyl group, described low alkyl group is replaced by one or more halogens; Or R
2and R
3together with the N atom connecting with them, form the heterocycloalkyl with 4 or 5 carbon atoms, one or more substituting groups that described Heterocyclylalkyl is optionally selected from halogen or low alkyl group replace, and described low alkyl group is replaced by one or more halogens;
X Shi – CH
2-Huo – (CH
2)
2-;
Ar is phenyl or pyridyl;
R
4it is halogen; Low alkyl group; The low alkyl group being replaced by one or more halogens; Or lower alkoxy;
N is 1 or 2;
Collateral condition be described compound not:
-5-(4-(3-luorobenzyl) piperazine-1-yl)-3-methyl isophthalic acid, 2,4-thiadiazoles and
-3-sec.-propyl-5-(4-(3-(trifluoromethyl) benzyl) piperazine-1-yl)-1,2,4-thiadiazoles.
2. formula IA compound according to claim 1, wherein X Shi – (CH
2)
2-.
3. formula IA compound according to claim 2, described compound is
1-[3-(the fluoro-piperidin-1-yl of 4,4-bis-)-[1,2,4] thiadiazoles-5-yl]-4-[2-(4-methoxyl group-phenyl)-ethyl]-piperazine
1-[2-(the chloro-phenyl of 4-)-ethyl]-4-[3-(the fluoro-piperidin-1-yl of 4,4-bis-)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the chloro-phenyl of 4-)-ethyl]-4-[3-(the fluoro-pyrrolidin-1-yl of 3,3-bis-)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the chloro-phenyl of 4-)-ethyl]-4-[3-(4-fluoro-piperidine-1-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the chloro-phenyl of 4-)-ethyl]-4-[3-(4-trifluoromethyl-piperidin-1-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the chloro-phenyl of 4-)-ethyl]-4-(3-piperidin-1-yl-[1,2,4] thiadiazoles-5-yl)-piperazine
(5-{4-[2-(the chloro-phenyl of 4-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-cyclopropyl methyl-amine
(5-{4-[2-(the chloro-phenyl of 4-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-(tetrahydrochysene-pyrans-4-yl)-amine
(5-{4-[2-(the chloro-phenyl of 4-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-cyclohexyl-amine
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(the fluoro-piperidin-1-yl of 4,4-bis-)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(the fluoro-pyrrolidin-1-yl of 3,3-bis-)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(4-fluoro-piperidine-1-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(4-trifluoromethyl-piperidin-1-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-(3-pyrrolidin-1-yl-[1,2,4] thiadiazoles-5-yl)-piperazine
Cyclopropyl methyl-(5-{4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-amine
(5-{4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-(tetrahydrochysene-pyrans-4-yl)-amine
Cyclohexyl-(5-{4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-amine
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-(3-piperidin-1-yl-[1,2,4] thiadiazoles-5-yl)-piperazine
(5-{4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-(4-trifluoromethyl-cyclohexyl)-amine
Butyl-(5-{4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-ethyl-amine
1-(3-cyclohexyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(4-methoxyl group-phenyl)-ethyl]-piperazine
1-(3-cyclohexyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(3-methoxyl group-phenyl)-ethyl]-piperazine
1-(3-butyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(4-methoxyl group-phenyl)-ethyl]-piperazine
1-(3-cyclopropyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(4-methoxyl group-phenyl)-ethyl]-piperazine
1-(3-butyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(3-methoxyl group-phenyl)-ethyl]-piperazine
1-(3-cyclopropyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(3-methoxyl group-phenyl)-ethyl]-piperazine
1-[2-(the fluoro-phenyl of 4-)-ethyl]-4-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(4-methoxyl group-phenyl)-ethyl]-4-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(2-methoxyl group-pyridin-4-yl)-ethyl]-4-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
3-((3-chlorophenoxy) methyl)-5-(4-(3-anisole ethyl) piperazine-1-yl)-1,2,4-thiadiazoles
3-(2-(benzyloxy) ethyl)-5-(4-(3-anisole ethyl) piperazine-1-yl)-1,2,4-thiadiazoles
3-((4-fluorophenoxy) methyl)-5-(4-(3-anisole ethyl) piperazine-1-yl)-1,2,4-thiadiazoles
3-((4-fluorophenoxy) methyl)-5-(4-(4-anisole ethyl) piperazine-1-yl)-1,2,4-thiadiazoles or
5-(4-(4-anisole ethyl) piperazine-1-yl)-3-(trifluoromethyl)-1,2,4-thiadiazoles.
4. according to the formula IA compound described in any one in claim 1 – 3, wherein G
1it is low alkyl group; Cycloalkyl; Tetrahydropyran-4-base; The phenoxymethyl being replaced by one or more halogens; Benzyloxy-ethyl; Or the benzyloxy-ethyl being replaced by one or more halogens.
5. formula IA compound according to claim 4, wherein compound is
1-(3-cyclohexyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(4-methoxyl group-phenyl)-ethyl]-piperazine
1-(3-cyclohexyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(3-methoxyl group-phenyl)-ethyl]-piperazine
1-(3-butyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(4-methoxyl group-phenyl)-ethyl]-piperazine
1-(3-cyclopropyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(4-methoxyl group-phenyl)-ethyl]-piperazine
1-(3-butyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(3-methoxyl group-phenyl)-ethyl]-piperazine
1-(3-cyclopropyl-[1,2,4] thiadiazoles-5-yl)-4-[2-(3-methoxyl group-phenyl)-ethyl]-piperazine
1-[2-(the fluoro-phenyl of 4-)-ethyl]-4-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(4-methoxyl group-phenyl)-ethyl]-4-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(2-methoxyl group-pyridin-4-yl)-ethyl]-4-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(tetrahydrochysene-pyrans-4-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine or
3-((3-chlorophenoxy) methyl)-5-(4-(3-anisole ethyl) piperazine-1-yl)-1,2,4-thiadiazoles
3-(2-(benzyloxy) ethyl)-5-(4-(3-anisole ethyl) piperazine-1-yl)-1,2,4-thiadiazoles
3-((4-chlorophenoxy) methyl)-5-(4-(3-anisole ethyl) piperazine-1-yl)-1,2,4-thiadiazoles or
3-((4-fluorophenoxy) methyl)-5-(4-(4-anisole ethyl) piperazine-1-yl)-1,2,4-thiadiazoles.
6. according to the formula IA compound described in claim 1 – 3 any one, wherein G
1shi – NR
2r
3.
7. formula IA compound according to claim 6, wherein R
2hydrogen and R
3low alkyl group, tetrahydropyran-4-base ,-CH
2-cycloalkyl or the cycloalkyl optionally being replaced by low alkyl group, described low alkyl group is replaced by one or more halogens.
8. formula IA compound according to claim 7, wherein compound is
(5-{4-[2-(the chloro-phenyl of 4-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-cyclopropyl methyl-amine
(5-{4-[2-(the chloro-phenyl of 4-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-(tetrahydrochysene-pyrans-4-yl)-amine
(5-{4-[2-(the chloro-phenyl of 4-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-cyclohexyl-amine
Cyclopropyl methyl-(5-{4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-amine
(5-{4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-(tetrahydrochysene-pyrans-4-yl)-amine
Cyclohexyl-(5-{4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-amine or
(5-{4-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-piperazine-1-yl }-[1,2,4] thiadiazoles-3-yl)-(4-trifluoromethyl-cyclohexyl)-amine
9. formula IA compound according to claim 6, wherein R
2and R
3together with the N atom connecting with them, form the heterocycloalkyl with 4 or 5 carbon atoms, one or more substituting groups that described Heterocyclylalkyl is optionally selected from halogen or low alkyl group replace, and described low alkyl group is replaced by one or more halogens.
10. formula IA compound according to claim 9, described compound is
1-[3-(the fluoro-piperidin-1-yl of 4,4-bis-)-[1,2,4] thiadiazoles-5-yl]-4-[2-(4-methoxyl group-phenyl)-ethyl]-piperazine
1-[2-(the chloro-phenyl of 4-)-ethyl]-4-[3-(the fluoro-piperidin-1-yl of 4,4-bis-)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the chloro-phenyl of 4-)-ethyl]-4-[3-(the fluoro-pyrrolidin-1-yl of 3,3-bis-)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the chloro-phenyl of 4-)-ethyl]-4-[3-(4-fluoro-piperidine-1-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the chloro-phenyl of 4-)-ethyl]-4-[3-(4-trifluoromethyl-piperidin-1-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the chloro-phenyl of 4-)-ethyl]-4-(3-piperidin-1-yl-[1,2,4] thiadiazoles-5-yl)-piperazine
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(the fluoro-piperidin-1-yl of 4,4-bis-)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(the fluoro-pyrrolidin-1-yl of 3,3-bis-)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(4-fluoro-piperidine-1-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-[3-(4-trifluoromethyl-piperidin-1-yl)-[1,2,4] thiadiazoles-5-yl]-piperazine
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-(3-pyrrolidin-1-yl-[1,2,4] thiadiazoles-5-yl)-piperazine
1-[2-(the fluoro-phenyl of 3,4-bis-)-ethyl]-4-(3-piperidin-1-yl-[1,2,4] thiadiazoles-5-yl)-piperazine
11. 1 kinds for the preparation of according to the method for the formula IA compound described in claim 1-10 any one, and it comprises
By formula
Compound and formula
Compound coupling is to obtain formula
Wherein definition as described in claim 1, if wherein PG is that hydrogen or blocking group and hal are halogen or needs, is converted into pharmaceutically acceptable acid salt by described compound.
12. according to the compound described in any one in claim 1-10, its method preparation according to claim 11.
13. according to the compound described in any one in claim 1 – 10 or 12, and it is as therapeutic active substance.
14. 1 kinds of medicaments, it is containing one or more compounds and pharmaceutically acceptable vehicle described in any one in good grounds claim 1-10 or 12.
15. according to the compound described in any one in claim 1-10 or 12 or medicament according to claim 14, it is used for the treatment of and is selected from following disease: alzheimer's disease, pager's disease, corticobasal degeneration, stein-leventhal syndrome, frontotemporal dementia FTD and parkinsonism (are connected to karyomit(e) 17, FTDP-17).
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| EP1705474B1 (en) | 2005-03-21 | 2010-04-28 | F.Hoffmann-La Roche Ag | Method for determining lipophilicity |
| PE20070099A1 (en) * | 2005-06-30 | 2007-02-06 | Janssen Pharmaceutica Nv | N-HETEROARYLPIPERAZINYL UREAS AS MODULATORS OF FATTY ACID AMIDE HYDROLASE |
| WO2013004642A1 (en) * | 2011-07-01 | 2013-01-10 | Remynd Nv | 1, 2, 4 -thiadiazol- 5 -ylpiperazine derivatives useful in the treatment neurodegenerative diseases |
| EP2744798B1 (en) | 2011-08-17 | 2016-03-30 | reMynd NV | Piperazine thiazole derivatives useful in the treatment of tauopathies such as alzheimer's disease |
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| CN101137363A (en) * | 2005-01-07 | 2008-03-05 | 弗·哈夫曼-拉罗切有限公司 | [4-(heteroaryl)piperazin-1-yl]-(2,5-substituted -phenyl)methanone derivatives as glycine transporter 1 (Glyt-1) inhibitors for the treatment of neurological and neuropsychiatric disorders |
| CN101378757A (en) * | 2006-02-07 | 2009-03-04 | 瑞敏德股份有限公司 | Thiadiazole derivatives for the treatment of neuro degenerative diseases |
| WO2008099210A2 (en) * | 2007-02-12 | 2008-08-21 | Merck & Co., Inc. | Piperazine derivatives for treatment of ad and related conditions |
Also Published As
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|---|---|
| US9187440B2 (en) | 2015-11-17 |
| US20160101102A1 (en) | 2016-04-14 |
| AU2012296804B2 (en) | 2017-04-20 |
| EP2744798B1 (en) | 2016-03-30 |
| JP6051218B2 (en) | 2016-12-27 |
| CA2841037A1 (en) | 2013-02-21 |
| EP2744798A1 (en) | 2014-06-25 |
| PL2744798T3 (en) | 2016-08-31 |
| CA2841037C (en) | 2020-03-31 |
| WO2013024168A1 (en) | 2013-02-21 |
| AU2012296804A1 (en) | 2014-01-30 |
| US20140206699A1 (en) | 2014-07-24 |
| US9808456B2 (en) | 2017-11-07 |
| JP2014521737A (en) | 2014-08-28 |
| ES2573299T3 (en) | 2016-06-07 |
| HK1192848A1 (en) | 2014-09-05 |
| CN103649062B (en) | 2015-10-07 |
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